JP5881659B2 - Glucose-dependent insulinotropic polypeptide analog - Google Patents
Glucose-dependent insulinotropic polypeptide analog Download PDFInfo
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- JP5881659B2 JP5881659B2 JP2013207160A JP2013207160A JP5881659B2 JP 5881659 B2 JP5881659 B2 JP 5881659B2 JP 2013207160 A JP2013207160 A JP 2013207160A JP 2013207160 A JP2013207160 A JP 2013207160A JP 5881659 B2 JP5881659 B2 JP 5881659B2
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Description
本発明は、グルコース依存性インスリン分泌刺激(insulinotropic)ポリペプチドの新規のアナログ、前記化合物を含む医薬組成物、および前記化合物の、GIP受容体に仲介される病気、例えばインスリン非依存性糖尿病および肥満の治療のためのGIP受容体作動薬または拮抗薬としての使用の領域に関する。 The present invention relates to novel analogs of glucose-dependent insulinotropic polypeptides, pharmaceutical compositions comprising said compounds, and diseases of said compounds mediated by GIP receptors, such as non-insulin dependent diabetes mellitus and obesity Relates to the field of use as GIP receptor agonists or antagonists for the treatment of psoriasis.
グルコース依存性インスリン分泌刺激ポリペプチド(“GIP”、“胃抑制性ポリペプチド”としても知られている;SEQ ID NO:1)は、小腸の腸管内分泌(enteroendorine)K
細胞により、経口栄養摂取に応答して血流中に分泌される42残基のペプチドである。GIPは胃酸の分泌を抑制し、それは経口グルコース摂取の後の膵ベータ細胞からのインスリンの分泌に関する強力な刺激薬であることが示されている(“インクレチン作用”)(Creutzfeldt, W., et al., 1979, Diabetologia, 16:75-85)。
Glucose-dependent insulinotropic polypeptide (also known as “GIP”, “gastric inhibitory polypeptide”; SEQ ID NO: 1)
A 42-residue peptide that is secreted into the bloodstream by cells in response to oral nutrition. GIP inhibits gastric acid secretion, which has been shown to be a potent stimulator of insulin secretion from pancreatic beta cells following oral glucose ingestion (“incretin action”) (Creutzfeldt, W., et al., 1979, Diabetologia, 16: 75-85).
グルコースおよび他の栄養素の摂取により誘導されるインスリンの放出は、ホルモン性および神経性の要因の両方によるものである(Creutzfeldt, W., et al., 1985, Diabetologia, 28:565-573)。いくつかの胃腸調節ペプチドがインクレチン類として提案されて
おり、これらの候補の中で、GIPおよびグルカゴン様ペプチド1(“GLP−1”)のみが食後のインスリン放出の生理的刺激薬であると考えられるための必要条件を満たすようである(Nauck, et al., 1989, J. Clin. Endorinol. Metab., 69:654-662)。GIP
およびGLP−1の合同の作用は、腸膵島軸(enteroinsular axis)の完全なインクレチン作用を説明するのに十分であることが示されている(Fehmann, H. C., et al., 1989, FEBS Lett., 252:109-112)。
Insulin release induced by ingestion of glucose and other nutrients is due to both hormonal and neurological factors (Creutzfeldt, W., et al., 1985, Diabetologia, 28: 565-573). Several gastrointestinal regulatory peptides have been proposed as incretins, and among these candidates, only GIP and glucagon-like peptide 1 ("GLP-1") are physiological stimulators of postprandial insulin release. It seems to meet the requirements to be considered (Nauck, et al., 1989, J. Clin. Endorinol. Metab., 69: 654-662). GIP
The combined action of GLP-1 and GLP-1 has been shown to be sufficient to explain the complete incretin action of the enteroinsular axis (Fehmann, HC, et al., 1989, FEBS Lett ., 252: 109-112).
当業者には周知であるように、GIPの既知の、および可能性のある用途は様々であり、多様である。従って、この発明の化合物の、作動薬作用を誘発するための投与は、GIP自体と同じ作用および用途を有し得る。GIPのこれらの様々な用途は次のように要約することができる:1型糖尿病、2型糖尿病(Visboll, T., 2004, Dan. Med. Bull., 51:364-70)、インスリン抵抗性(WO 2005/082928)、肥満(Green, B. D.,
et al., 2004, Current Pharmaceutical Design, 10:3651-3662)、代謝障害(Gault, V. A., et al., 2003, BioChem. Biophys. Res. Commun., 308:207-213)、中枢神経系疾
患、神経変性疾患、うっ血性心不全、低血糖症、ならびに摂食の減少および体重の低下が望まれる障害からなるグループから選択される疾患の治療。膵島において、GIPはインスリンの分泌を急激に増進するだけでなく、それはプロインスリンの転写および翻訳の増進を通してインスリンの産生も刺激し(Wang, et al., 1996, Mol. Cell. Endocrinol., 116:81-87)、膵ベータ細胞の成長および生存を増進する(Trumper, et al., 2003, Diabetes, 52:741-750)。膵臓に対するインスリンの分泌を増進する作用に加え、GIPはインスリンの標的組織にも直接作用して血漿グルコースを低下させる:脂肪(Eckel, et al., 1979, Diabetes, 28:1141-1142)および筋肉(O’Harte, et al., 1998, J. Endocrinol., 156:237-243)におけるグルコースの取り込みの増進、ならびに肝臓のグルコースの生成の抑制(Elahi, D., et al., 1986, Can.J. Physiol. Pharmacol., 65:A18)。
As is well known to those skilled in the art, the known and potential uses of GIP are various and diverse. Thus, administration of the compounds of this invention to induce agonist effects may have the same effects and uses as GIP itself. These various uses of GIP can be summarized as follows: Type 1 diabetes, Type 2 diabetes (Visboll, T., 2004, Dan. Med. Bull., 51: 364-70), insulin resistance (WO 2005/082928), obesity (Green, BD,
et al., 2004, Current Pharmaceutical Design, 10: 3651-3662), metabolic disorders (Gault, VA, et al., 2003, BioChem. Biophys. Res. Commun., 308: 207-213), central nervous system diseases Treatment of a disease selected from the group consisting of: neurodegenerative diseases, congestive heart failure, hypoglycemia, and disorders where reduced feeding and weight loss are desired. In pancreatic islets, GIP not only dramatically increases insulin secretion, but it also stimulates insulin production through enhanced transcription and translation of proinsulin (Wang, et al., 1996, Mol. Cell. Endocrinol., 116 : 81-87), enhances pancreatic beta cell growth and survival (Trumper, et al., 2003, Diabetes, 52: 741-750). In addition to enhancing insulin secretion to the pancreas, GIP also acts directly on the target tissue of insulin to lower plasma glucose: fat (Eckel, et al., 1979, Diabetes, 28: 1141-1142) and muscle (O'Harte, et al., 1998, J. Endocrinol., 156: 237-243) enhanced glucose uptake as well as suppression of hepatic glucose production (Elahi, D., et al., 1986, Can J. Physiol. Pharmacol., 65: A18).
加えて、本発明に従うGIP受容体拮抗薬は、動物の腸からのグルコースの吸収を抑制、阻止または低減する。この観察に従い、GIP拮抗薬を含む療法組成物は、インスリン非依存性糖尿病を有する患者において経口グルコースに対する耐性を向上させるために、哺乳類、例えばヒトにおいて、その哺乳類の腸からのグルコースの吸収を抑制、阻止または低減することにより肥満を予防、抑制または低減するために用いられてよい。 In addition, GIP receptor antagonists according to the present invention inhibit, block or reduce the absorption of glucose from the intestines of animals. In accordance with this observation, a therapeutic composition comprising a GIP antagonist inhibits glucose absorption from the gut of a mammal in a mammal, eg, a human, to improve tolerance to oral glucose in patients with non-insulin dependent diabetes It can be used to prevent, suppress or reduce obesity by preventing or reducing.
しかし、修飾されていないGIPの療法薬としての使用は、約2分というインビボでの短い半減期により制限される(Said and Mutt, 1970, Science, 169:1217-1218)。血清
中では、インクレチン類GIPおよびGLP−1は共にジペプチジルペプチダーゼIV(“DPPIV”)により分解される。GIPのタンパク質分解に対する安定性の向上は、その受容体におけるGIPの活性を維持するだけでなく、これがさらに重要なのだが、その一部がGIP受容体の拮抗薬として働くGIP断片の生成を防ぐ(Gault, et al., 2002, J. Endocrinol., 175:525-533)。報告された修飾には、N末端のチロシンの修飾(O
’Harte, et al., 2002, Diabetologia, 45:1281-1291)、2位のアラニンの変異(Hinke, et al., 2002, Diabetes, 51:656-661)3位のグルタミン酸の変異(Gault, et al., 2003, BioChem. Biophys. Res. Commun., 308:207-213)、および13位のアラニンの変異(Gault, et al., 2003, Cell Biol. International, 27:41-46)を通した、GIPのN
末端のDPPIVによるタンパク質分解からの保護が含まれていた。
However, the use of unmodified GIP as a therapeutic is limited by a short half-life in vivo of approximately 2 minutes (Said and Mutt, 1970, Science, 169: 1217-1218). In serum, both the incretins GIP and GLP-1 are degraded by dipeptidyl peptidase IV (“DPPIV”). Improved stability to proteolysis of GIP not only maintains GIP activity at its receptor, but, more importantly, prevents the generation of GIP fragments, some of which act as antagonists of the GIP receptor ( Gault, et al., 2002, J. Endocrinol., 175: 525-533). The reported modifications include N-terminal tyrosine modifications (O
'Harte, et al., 2002, Diabetologia, 45: 1281-1291) Alanine mutation at position 2 (Hinke, et al., 2002, Diabetes, 51: 656-661) Glutamate mutation at position 3 (Gault, et al., 2003, BioChem. Biophys. Res. Commun., 308: 207-213), and alanine mutation at position 13 (Gault, et al., 2003, Cell Biol. International, 27: 41-46) GIP N
Protection from proteolysis by terminal DPPIV was included.
下記の特許出願は、GIPアナログの様々な標的器官の機能に対する作用およびそれらの療法薬としての使用の可能性に関して出願された:
PCT公開WO 00/58360は、インスリンの放出を刺激するGIPのペプチジルアナログを開示している。特に、この出願はGIP(1-42)のN末端から少なくとも15ア
ミノ酸残基を含む特定のペプチジルアナログ、例えば1、2および3位において正確に1アミノ酸の置換または修飾を含むGIPのアナログ、例えば[Pro3]GIP(1-42)を開示して
いる。
The following patent applications were filed regarding the effects of GIP analogs on the function of various target organs and their potential use as therapeutic agents:
PCT publication WO 00/58360 discloses peptidyl analogs of GIP that stimulate the release of insulin. In particular, this application describes certain peptidyl analogs that contain at least 15 amino acid residues from the N-terminus of GIP (1-42), such as GIP analogs that contain exactly one amino acid substitution or modification at positions 1, 2, and 3, for example [Pro 3 ] GIP (1-42) is disclosed.
PCT公開WO 98/24464は、本質的にGIPの配列の7〜30位に対応する24アミノ酸のポリペプチドで構成されるGIPの拮抗薬、インスリン非依存性糖尿病を治療する方法、およびインスリン非依存性糖尿病の患者においてグルコース耐性を向上させる方法を開示している。 PCT Publication WO 98/24464 is a GIP antagonist consisting essentially of a 24 amino acid polypeptide corresponding to positions 7-30 of the GIP sequence, a method of treating insulin-independent diabetes, and insulin-independent For improving glucose tolerance in patients with diabetes mellitus.
PCT公開WO 03/082898は、GIPのC末端を切り詰めた断片およびN末端を修飾したアナログ、ならびにDPPIV特異的切断部位の近くに還元されたペプチド結合またはアミノ酸の変更を有する様々なGIPアナログを開示している。この出願はさらに、GIPの可能性のある受容体結合部位の間に異なるリンカーを有するアナログを開示している。この出願の化合物は、GIP受容体に仲介される病気、例えばインスリン非依存性糖尿病および肥満の治療において有用であると主張されている。 PCT Publication WO 03/082898 discloses GIP C-terminal truncated fragments and N-terminal modified analogs and various GIP analogs with reduced peptide bonds or amino acid changes near the DPPIV specific cleavage site. doing. This application further discloses analogs having different linkers between potential receptor binding sites of GIP. The compounds of this application are claimed to be useful in the treatment of diseases mediated by GIP receptors such as non-insulin dependent diabetes and obesity.
配合物中で安定であり、タンパク質分解に対する感受性の低下およびクリアランスの低下の結果もたらされるインビボでの長い血漿内半減期を有する一方でそれぞれの作動薬または拮抗薬作用を誘発するためのGIP受容体への結合親和性を維持している、GIPの改良されたアナログに関する必要性が存在する。さらに、本明細書で説明する本発明の化合物の他の療法的作用の中で、血漿グルコースレベルのより厳重な制御は、長期の糖尿病性合併症を予防し、それにより患者に改善された生活の質を提供する可能性がある。 GIP receptors for eliciting the respective agonist or antagonist action while being stable in the formulation and having a long in vivo plasma half-life resulting from reduced susceptibility to proteolysis and reduced clearance There is a need for improved analogs of GIP that maintain binding affinity for. Moreover, among other therapeutic effects of the compounds of the present invention described herein, tighter control of plasma glucose levels prevents long-term diabetic complications, thereby improving patient life. There is a possibility of providing quality.
1観点において、本発明は次の式(I)のGIPのペプチド変種に関し:
(R2R3)-Tyr-Ala-Glu-A4-A5-A6-A7-A8-A9-A10-A11-A12A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-A42-A43-R1、
(I)
ここで:
A4はGly、Acc、Aib、またはβ-Alaであり;
A5はThr、Acc、Aib、またはSerであり;
A6はPhe、Acc、Aib、Aic、Cha、1Nal、2Nal、2-Pal、3-Pal、4-Pal、(X4,X5,X6,X7,X8)PheまたはTrpであり;
A7はIle、Abu、Acc、Aib、Ala、Cha、Leu、Nle、Phe、Tle、またはValであり;
A8はSer、Aib、またはThrであり;
A9はAsp、Aib、またはGluであり;
A10はTyr、Acc、Cha、1Nal、2Nal、2-Pal、3-Pal、4-Pal、Phe、または(X4,X5,X6,X7,X8)Pheであり;
A11はSer、Acc、Aib、NleまたはThrであり;
A12はIle、Abu、Acc、Aib、Ala、Cha、Leu、Nle、Phe、Tle、またはValであり;
A13はAla、Acc、Aib、β-Ala、D-Ala、Gly、またはSerであり;
A14はMet、Abu、Acc、Aib、Ala、Cha、Ile、Leu、Nle、Phe、Tle、またはValであり;
A15はAsp、Aib、またはGluであり;
A16はLys、Amp、Apc、Arg、hArg、Orn、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スク
シンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、またはPen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり;
A17はIle、Abu、Acc、Aib、Ala、Cha、Leu、Nle、Phe、Tle、またはValであり;
A18はHis、Amp、Arg、2-Pal、3-Pal、または4-Pal、Phe、またはTyrであり;
A19はGln、Aib、またはAsnであり;
A20はGln、Aib、またはAsnであり;
A21はAsp、Aib、またはGluであり;
A22はPhe、Acc、Aib、Aic、Cha、1Nal、2Nal、2-Pal、3-Pal、4-Pal、(X4,X5,X6,X7,X8)Phe、またはTrpであり;
A23はVal、Abu、Acc、Aib、Ala、Cha、Ile、Leu、Nle、またはTleであり;
A24はAsn、Aib、またはGlnであり;
A25はTrp、Acc、Aib、1Nal、2Nal、2-Pal、3-Pal、4-Pal、Phe、または(X4,X5,X6,X7,X8)Pheであり;
A26はLeu、Acc、Aib、Cha、Ile、Nle、Phe、(X4,X5,X6,X7,X8)PheまたはTleであり;
A27はLeu、Acc、Aib、Cha、Ile、Nle、Phe、(X4,X5,X6,X7,X8)PheまたはTleであり;
A28はAla、Aib、またはAccであり;
A29はGln、Aib、Asnであり、または欠失しており;
A30はLys、Amp、Apc、Arg、hArg、Orn、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スク
シンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
A31はGly、Acc、Aib、β-Ala、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-
アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、His、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失してお
り;
A32はLys、Amp、Apc、Arg、hArg、Cys、Orn、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スク
シンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠
失しており;
A33はLys、Amp、Apc、Arg、hArg、Cys、Orn、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スク
シンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠
失しており;
A34はAsn、Aib、Gln、Ser、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
A35はAsp、Aib、Glu、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシン
イミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(
スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
A36はTrp、Acc、Aib、1Nal、2Nal、2-Pal、3-Pal、4-Pal、Phe、(X4,X5,X6,X7,X8)Phe
、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミ
ド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシン
イミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
A37はLys、Amp、Apc、Arg、hArg、Orn、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スク
シンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
A38はHis、Amp、2-Pal、3-Pal、4-Pal、Phe、Tyr、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミ
ド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
A39はAsn、Aib、Gln、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシン
イミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(
スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
A40はIle、Acc、Aib、Ser、Thr、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイ
ミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
A41はThr、Aib、Acc、Asn、Gln、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイ
ミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
A42はGln、Acc、Aib、Asn、HN-CH((CH2)n-N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
A43はAcc、Ado、Aib、Ala、Asn、Asp、Cys、Gln、His、Phe、Thr、Trp、HN-CH((CH2)n-
N(R4R5))-C(O)、Cys(スクシンイミド-N-アルキル)、hCys(スクシンイミド-N-アルキル)、Pen(スクシンイミド-N-アルキル)、Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)
、hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)、Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、hCys(スク
シンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)、Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)であり、または欠失しており;
R1はOH、NH2、(C1-C30)アルコキシ、またはNH-X2-CH2-Z0であり、ここでX2は(C0-C30)
炭化水素部分であり、Z0はH、OH、CO2H、またはCONH2であり;
R2、R3、R4およびR5のそれぞれはH、(C1-C30)アルキル、(C1-C30)ヘテロアルキル、(C1-C30)アシル、(C2-C30)アルケニル、(C2-C30)アルキニル、アリール(C1-C30)アルキル、
アリール(C1-C30)アシル、置換された(C1-C30)アルキル、置換された(C1-C30)ヘテロアルキル、置換された(C1-C30)アシル、置換された(C2-C30)アルケニル、置換された(C2-C30)アルキニル、置換されたアリール(C1-C30)アルキル、および置換されたアリール(C1-C30)アシルからなるグループから独立して選択され;R2が(C1-C30)アシル、アリール(C1-C30)アシル、置換された(C1-C30)アシル、または置換されたアリール(C1-C30)アシルである場合、R3はH、(C1-C30)アルキル、(C1-C30)ヘテロアルキル、(C2-C30)アルケニル、(C2-C30)アルキニル、アリール(C1-C30)アルキル、置換された(C1-C30)アルキル、置換された(C1-C30)ヘテロアルキル、置換された(C2-C30)アルケニル、置換された(C2-C30)アルキニル
、または置換されたアリール(C1-C30)アルキルであり;さらにR4が(C1-C30)アシル、アリール(C1-C30)アシル、置換された(C1-C30)アシル、または置換されたアリール(C1-C30)アシルである場合、R5はH、(C1-C30)アルキル、(C1-C30)ヘテロアルキル、(C2-C30)アルケ
ニル、(C2-C30)アルキニル、アリール(C1-C30)アルキル、置換された(C1-C30)アルキル、置換された(C1-C30)ヘテロアルキル、置換された(C2-C30)アルケニル、置換された(C2-C30)アルキニル、または置換されたアリール(C1-C30)アルキルであり;
nは、それぞれの出現に関して独立して1と5を含めた1から5までの整数であり;
s、t、xおよびyのそれぞれは、それぞれの出現に関して独立して1と30を含めた1から30までの整数であり;ならびに
X4、X5、X6、X7およびX8のそれぞれは、それぞれの出現に関して独立してH、F、Cl、Br、I、(C1-10)アルキル、置換された(C1-10)アルキル、アリール、置換されたアリール、OH、NH2、NO2、またはCNである。
In one aspect, the invention relates to a peptide variant of GIP of the following formula (I):
(R 2 R 3 ) -Tyr-Ala-Glu-A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 32 -A 33 -A 34 -A 35 -A 36 -A 37 -A 38 -A 39 -A 40 -A 41 -A 42 -A 43 -R 1 ,
(I)
here:
A 4 is Gly, Acc, Aib, or β-Ala;
A 5 is Thr, Acc, Aib, or Ser;
A 6 is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X 4 , X 5 , X 6 , X 7 , X 8 ) Phe or Trp ;
A 7 is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val;
A 8 is Ser, Aib, or Thr;
A 9 is Asp, Aib, or Glu;
A 10 is Tyr, Acc, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or (X 4 , X 5 , X 6 , X 7 , X 8 ) Phe;
A 11 is Ser, Acc, Aib, Nle or Thr;
A 12 is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val;
A 13 is Ala, Acc, Aib, β-Ala, D-Ala, Gly, or Ser;
A 14 is Met, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, Phe, Tle, or Val;
A 15 is Asp, Aib, or Glu;
A 16 is Lys, Amp, Apc, Arg, hArg, Orn, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys ( Succinimide-N-alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N -(CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Cys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O) -(CH 2 ) t -CH 3 ), or Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 );
A 17 is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val;
A 18 is His, Amp, Arg, 2-Pal, 3-Pal, or 4-Pal, Phe, or Tyr;
A 19 is Gln, Aib, or Asn;
A 20 is Gln, Aib, or Asn;
A 21 is Asp, Aib, or Glu;
A 22 is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X 4 , X 5 , X 6 , X 7 , X 8 ) Phe, or Trp Yes;
A 23 is Val, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, or Tle;
A 24 is Asn, Aib, or Gln;
A 25 is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or (X 4 , X 5 , X 6 , X 7 , X 8 ) Phe;
A 26 is Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X 4 , X 5 , X 6 , X 7 , X 8 ) Phe or Tle;
A 27 is Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X 4 , X 5 , X 6 , X 7 , X 8 ) Phe or Tle;
A 28 is Ala, Aib, or Acc;
A 29 is Gln, Aib, Asn, or is deleted;
A 30 is Lys, Amp, Apc, Arg, hArg, Orn, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys ( Succinimide-N-alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N -(CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Cys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O) -(CH 2 ) t -CH 3 ), Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), or missing;
A 31 is Gly, Acc, Aib, β-Ala, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-
Alkyl), hCys (succinimide-N-alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2) y -CH 3), Cys ( succinimide -N- (CH 2) s -NH- C (O) - (CH 2) t -CH 3), hCys ( succinimide -N- (CH 2) s -NH -C (O)-(CH 2 ) t -CH 3 ), His, Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), or Missing;
A 32 is Lys, Amp, Apc, Arg, hArg, Cys, Orn, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys (succinimide-N-alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide) -N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Cys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C ( O)-(CH 2 ) t -CH 3 ), Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), or missing ;
A 33 is Lys, Amp, Apc, Arg, hArg, Cys, Orn, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys (succinimide-N-alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide) -N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Cys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C ( O)-(CH 2 ) t -CH 3 ), Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), or missing ;
A 34 is Asn, Aib, Gln, Ser, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys (succinimide-N- Alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Cys (Succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), or deleted;
A 35 is Asp, Aib, Glu, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys (succinimide-N-alkyl) , Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Cys (succinimide -N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), Pen (
Succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ) or deleted;
A 36 is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, (X 4 , X 5 , X 6 , X 7 , X 8 ) Phe
, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys (succinimide-N-alkyl), Pen (succinimide-N-alkyl) ), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Cys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), Pen (succinimide -N- (CH 2) s -NH- C (O) - (CH 2) a t -CH 3), or is deleted with;
A 37 is Lys, Amp, Apc, Arg, hArg, Orn, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys ( Succinimide-N-alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N -(CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Cys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O) -(CH 2 ) t -CH 3 ), Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), or missing;
A 38 is His, Amp, 2-Pal, 3-Pal, 4-Pal, Phe, Tyr, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide) -N-alkyl), hCys (succinimide-N-alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH -(CH 2 ) y -CH 3 ), Cys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), Or is missing;
A 39 is Asn, Aib, Gln, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys (succinimide-N-alkyl) , Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Cys (succinimide -N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), Pen (
Succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ) or deleted;
A 40 is Ile, Acc, Aib, Ser, Thr, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys (succinimide- N-alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N- ( CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ) , Cys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O)-( CH 2 ) t -CH 3 ), Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), or missing;
A 41 is Thr, Aib, Acc, Asn, Gln, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys (succinimide- N-alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N- ( CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ) , Cys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O)-( CH 2 ) t -CH 3 ), Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), or missing;
A 42 is Gln, Acc, Aib, Asn, HN-CH ((CH 2 ) n -N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys (succinimide-N- Alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), hCys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Cys (Succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), or deleted;
A 43 is Acc, Ado, Aib, Ala, Asn, Asp, Cys, Gln, His, Phe, Thr, Trp, HN-CH ((CH 2 ) n-
N (R 4 R 5 ))-C (O), Cys (succinimide-N-alkyl), hCys (succinimide-N-alkyl), Pen (succinimide-N-alkyl), Cys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 )
, HCys (succinimide-N- (CH 2 ) x -C (O) -NH- (CH 2 ) y -CH 3 ), Pen (succinimide-N- (CH 2 ) x -C (O) -NH- ( CH 2 ) y -CH 3 ), Cys (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), hCys (succinimide-N- (CH 2 ) s- NH-C (O)-(CH 2 ) t -CH 3 ), Pen (succinimide-N- (CH 2 ) s -NH-C (O)-(CH 2 ) t -CH 3 ), or missing Lost;
R 1 is OH, NH 2 , (C 1 -C 30 ) alkoxy, or NH-X 2 -CH 2 -Z 0 , where X 2 is (C 0 -C 30 )
A hydrocarbon moiety, Z 0 is H, OH, CO 2 H, or CONH 2 ;
Each of R 2 , R 3 , R 4 and R 5 is H, (C 1 -C 30 ) alkyl, (C 1 -C 30 ) heteroalkyl, (C 1 -C 30 ) acyl, (C 2 -C 30 ) Alkenyl, (C 2 -C 30 ) alkynyl, aryl (C 1 -C 30 ) alkyl,
Aryl (C 1 -C 30 ) acyl, substituted (C 1 -C 30 ) alkyl, substituted (C 1 -C 30 ) heteroalkyl, substituted (C 1 -C 30 ) acyl, substituted The group consisting of (C 2 -C 30 ) alkenyl, substituted (C 2 -C 30 ) alkynyl, substituted aryl (C 1 -C 30 ) alkyl, and substituted aryl (C 1 -C 30 ) acyl R 2 is (C 1 -C 30 ) acyl, aryl (C 1 -C 30 ) acyl, substituted (C 1 -C 30 ) acyl, or substituted aryl (C 1- When C 30 ) acyl, R 3 is H, (C 1 -C 30 ) alkyl, (C 1 -C 30 ) heteroalkyl, (C 2 -C 30 ) alkenyl, (C 2 -C 30 ) alkynyl, Aryl (C 1 -C 30 ) alkyl, substituted (C 1 -C 30 ) alkyl, substituted (C 1 -C 30 ) heteroalkyl, substituted (C 2 -C 30 ) alkenyl, substituted (C 2 -C 30 ) alkynyl, or substituted aryl (C 1 -C 30 ) alkyl; and R 4 is (C 1 -C 30 ) acyl, aryl (C 1 -C 30 ) acyl, substituted (C 1 -C 30 ) acyl, or substituted aryl ( When C 1 -C 30 ) acyl, R 5 is H, (C 1 -C 30 ) alkyl, (C 1 -C 30 ) heteroalkyl, (C 2 -C 30 ) alkenyl, (C 2 -C 30 ) Alkynyl, aryl (C 1 -C 30 ) alkyl, substituted (C 1 -C 30 ) alkyl, substituted (C 1 -C 30 ) heteroalkyl, substituted (C 2 -C 30 ) alkenyl, Substituted (C 2 -C 30 ) alkynyl, or substituted aryl (C 1 -C 30 ) alkyl;
n is an integer from 1 to 5 including 1 and 5 independently for each occurrence;
each of s, t, x and y is an integer from 1 to 30 including 1 and 30 independently for each occurrence; and
Each of X 4 , X 5 , X 6 , X 7 and X 8 is independently H, F, Cl, Br, I, (C 1-10 ) alkyl, substituted (C 1- 10) alkyl, aryl, substituted aryl, OH, NH 2, NO 2, or CN,.
上記の式(I)に含まれる化合物の部分集合(A)は下記のものである:
A4はGlyであり;
A5はThrであり;
A6はPheであり;
A7はIleまたはA6cであり;
A8はSerであり;
A9はAspであり;
A10はTyrであり;
A11はSer、A5c、またはA6cであり;
A12はIleであり;
A13はAlaまたはAibであり;
A14はMet、A5c、A6c、またはNleであり;
A15はAspであり;
A16はLysであり;
A17はIleであり;
A18はHisであり;
A19はGlnであり;
A20はGlnであり;
A21はAspであり;
A22はPheであり;
A23はValであり;
A24はAsnであり;
A25はTrpであり;
A26はLeuであり;
A27はLeuであり;
A28はAlaであり;
A29はGlnであり;
A30はLysであり;
A31はGly、His、Orn(N-C(O)-(CH2)12-CH3)であり、または欠失しており;
A32はLys、Cys、Cys(スクシンイミド-N-(CH2)11-CH3)、Cys(スクシンイミド-N-(CH2)15-CH3)、Orn(N-C(O)-(CH2)10-CH3)、Orn(N-C(O)-(CH2)14-CH3)であり、または欠失してお
り;
A33はLys、Cys、Cys(スクシンイミド-N-(CH2)11-CH3)、Cys(スクシンイミド-N-(CH2)15-CH3)、Orn(N-C(O)-(CH2)10-CH3)、またはOrn(N-C(O)-(CH2)14-CH3)であり、または欠失
しており;
A34はAsnであり、または欠失しており;
A35はAsp、Orn(N-C(O)-(CH2)12-CH3)であり、または欠失しており;
A36はTrpであり、または欠失しており;
A37はLysであり、または欠失しており;
A38はHisであり、または欠失しており;
A39はAsnであり、または欠失しており;
A40はIle、A5c、A6cであり、または欠失しており;
A41はThr、A5c、A6cであり、または欠失しており;
A42はGln、Cys(Psu)であり、または欠失しており;
A43はAdo、Ala、Asn、Asp、Cys、Cys(スクシンイミド-N-(CH2)11-CH3)、Cys(スクシン
イミド-N-(CH2)15-CH3)、His、Lys(N-C(O)-(CH2)10-CH3)、Lys(N-C(O)-(CH2)14-CH3)、Orn(N-C(O)-(CH2)14-CH3)、Phe、Thr、Trpであり、または欠失しており;
ただし、A7、A11、A13、A14、A31、A35、A40、A41およびA42の少なくとも1つは、天然のGIPの対応する位置のアミノ酸残基では無い。
A subset (A) of the compounds included in the above formula (I) is:
A 4 is Gly;
A 5 is Thr;
A 6 is Phe;
A 7 is Ile or A6c;
A 8 is Ser;
A 9 is Asp;
A 10 is Tyr;
A 11 is Ser, A5c, or A6c;
A 12 is Ile;
A 13 is Ala or Aib;
A 14 is Met, A5c, A6c, or Nle;
A 15 is Asp;
A 16 is Lys;
A 17 is Ile;
A 18 is His;
A 19 is Gln;
A 20 is Gln;
A 21 is Asp;
A 22 is Phe;
A 23 is Val;
A 24 is Asn;
A 25 is Trp;
A 26 is Leu;
A 27 is Leu;
A 28 is Ala;
A 29 is Gln;
A 30 is Lys;
A 31 is Gly, His, Orn (NC (O)-(CH 2 ) 12 -CH 3 ), or is deleted;
A 32 is Lys, Cys, Cys (succinimide-N- (CH 2 ) 11 -CH 3 ), Cys (succinimide-N- (CH 2 ) 15 -CH 3 ), Orn (NC (O)-(CH 2 ) 10 -CH 3 ), Orn (NC (O)-(CH 2 ) 14 -CH 3 ), or deleted;
A 33 is Lys, Cys, Cys (succinimide-N- (CH 2 ) 11 -CH 3 ), Cys (succinimide-N- (CH 2 ) 15 -CH 3 ), Orn (NC (O)-(CH 2 ) 10 -CH 3), or Orn (NC (O) - ( CH 2) 14 is -CH 3), or is deleted with;
A 34 is Asn or is deleted;
A 35 is Asp, Orn (NC (O)-(CH 2 ) 12 -CH 3 ), or is deleted;
A 36 is Trp or is deleted;
A 37 is Lys or is deleted;
A 38 is His or deleted;
A 39 is Asn or is deleted;
A 40 is Ile, A5c, A6c, or is deleted;
A 41 is Thr, A5c, A6c, or is deleted;
A 42 is Gln, Cys (Psu), or is deleted;
A 43 is Ado, Ala, Asn, Asp, Cys, Cys (succinimide-N- (CH 2 ) 11 -CH 3 ), Cys (succinimide-N- (CH 2 ) 15 -CH 3 ), His, Lys (NC (O)-(CH 2 ) 10 -CH 3 ), Lys (NC (O)-(CH 2 ) 14 -CH 3 ), Orn (NC (O)-(CH 2 ) 14 -CH 3 ), Phe, Thr, Trp, or deleted;
However, at least one of A 7 , A 11 , A 13 , A 14 , A 31 , A 35 , A 40 , A 41 and A 42 is not an amino acid residue at a corresponding position in natural GIP.
前記の部分集合(A)の化合物の部分集合は下記のものである:
A7はIleであり;
A13はAlaまたはAibであり;
A14はMet、A5c、A6c、またはNleであり;
A31はGlyであり;
A35はAspであり;および
A42はGlnである。
The subset of compounds of said subset (A) is:
A 7 is Ile;
A 13 is Ala or Aib;
A 14 is Met, A5c, A6c, or Nle;
A 31 is Gly;
A 35 is Asp; and
A 42 is Gln.
前記の部分集合(A)の化合物の部分集合は下記のものである:
A7はA6cであり;
A11はSerであり;
A13はAlaであり;
A14はMetまたはNleであり;
A31はGlyまたはOrn(N-C(O)-(CH2)12-CH3)であり;
A32はLysであり;
A33はLysであり;
A35はAspまたはOrn(N-C(O)-(CH2)12-CH3)であり;
A40はIleであり;
A41はThrまたはA6cであり;
A42はGlnまたはCys(Psu)であり;および
A43は欠失している。
The subset of compounds of said subset (A) is:
A 7 is A6c;
A 11 is Ser;
A 13 is Ala;
A 14 is Met or Nle;
A 31 is Gly or Orn (NC (O)-(CH 2 ) 12 -CH 3 );
A 32 is Lys;
A 33 is Lys;
A 35 is Asp or Orn (NC (O)-(CH 2 ) 12 -CH 3 );
A 40 is Ile;
A 41 is Thr or A6c;
A 42 is Gln or Cys (Psu); and
A 43 is missing.
式(I)の好ましい化合物は次のものである:
実施例1: (A5c11, 41)hGIP(1-42)-OH (SEQ ID NO:4);
実施例2: (A5c11, 40)hGIP(1-42)-OH (SEQ ID NO:5);
実施例3: (A5c11, His43)hGIP(1-43)-OH (SEQ ID NO:6);
実施例4: (A5c11, Asn43)hGIP(1-43)-OH (SEQ ID NO:7);
実施例5: (Aib13, Asp43)hGIP(1-43)-NH2 (SEQ ID NO:8);
実施例6: (Aib13, Nle14, A5c40)hGIP(1-42)-OH (SEQ ID NO:9);
実施例7: (Aib13, A5c40)hGIP(1-42)-OH (SEQ ID NO:10);
実施例8: (A5c11, Ala43)hGIP(1-43)-OH (SEQ ID NO:11);
実施例9: (Aib13, Nle14, Phe43)hGIP(1-43)-OH (SEQ ID NO:12);
実施例10: (A5c11, Thr43)hGIP(1-43)-OH (SEQ ID NO:13);
実施例11: (A6c11, 14, 41)hGIP(1-42)-OH (SEQ ID NO:14);
実施例12: (Aib13, Trp43)hGIP(1-43)-OH (SEQ ID NO:15);
実施例13: (A5c11, Ado43)hGIP(1-43)-OH (SEQ ID NO:16);
実施例14: (A6c11, 14, 40)hGIP(1-42)-OH (SEQ ID NO:17);
実施例15: [A6c7, Cys(Psu)42]hGIP(1-42)-OH (SEQ ID NO:18);
実施例16: (A6c7, 41)hGIP(1-42)-OH (SEQ ID NO:19);
実施例17: (A6c7, 41, Nle14)hGIP(1-42)-OH (SEQ ID NO:20);
実施例18: [A6c7, Orn35(N-C(O)-(CH2)12-CH3)]hGIP(1-42)-OH (SEQ ID NO:21);
実施例19: [A6c7, Orn31(N-C(O)-(CH2)12-CH3)]hGIP(1-42)-OH (SEQ ID NO:22);
実施例20: (A5c11, 14, His43)hGIP(1-43)-OH (SEQ ID NO:23);
実施例21: (A5c11, Nle14, His43)hGIP(1-43)-OH (SEQ ID NO:24);
実施例22: [A5c11, Orn32(N-C(O)-(CH2)14-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:25);
実施例23: [A5c11, Orn33(N-C(O)-(CH2)14-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:26);
実施例24: [A5c11, Orn43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH (SEQ ID NO:27);
実施例25: [A5c11, Cys32(スクシンイミド-N-(CH2)15-CH3), His43]hGIP(1-43)-OH
(SEQ ID NO:28);
実施例26: [A5c11, Cys33(スクシンイミド-N-(CH2)15-CH3), His43]hGIP(1-43)-OH
(SEQ ID NO:29);
実施例27: [A5c11, Cys43(スクシンイミド-N-(CH2)15-CH3)]hGIP(1-43)-OH (SEQ ID NO:30);
実施例28: (A5c11)hGIP(1-30)-NH2 (SEQ ID NO:31);
実施例29: (A5c11, His31)hGIP(1-31)-NH2 (SEQ ID NO:32);
実施例30: (A5c11, 14)hGIP(1-30)-NH2 (SEQ ID NO:33);
実施例31: (A5c11, 41, Cys32)hGIP(1-42)-NH2(SEQ ID NO:34);
実施例32: (A5c11, 41, Cys33)hGIP(1-42)-NH2(SEQ ID NO:35);
実施例33: (A5c11, 41, Cys43)hGIP(1-43)-NH2(SEQ ID NO:36);
実施例34: [A5c11, Orn32(N-C(O)-(CH2)10-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:37);
実施例35: [A5c11, Orn33(N-C(O)-(CH2)10-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:38);
実施例36: [A5c11, Lys43(N-C(O)-(CH2)10-CH3)]hGIP(1-43)-OH (SEQ ID NO:39);
実施例37: [A5c11, Cys32(スクシンイミド-N-(CH2)11-CH3), His43]hGIP(1-43)-OH
(SEQ ID NO:40);
実施例38: [A5c11, Cys33(スクシンイミド-N-(CH2)11-CH3), His43]hGIP(1-43)-OH
(SEQ ID NO:41);
実施例39: [A5c11, Cys43(スクシンイミド-N-(CH2)11-CH3)]hGIP(1-43)-OH (SEQ ID NO:42);
実施例40: [A5c11, Lys43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH (SEQ ID NO:43);
実施例41: [A5c11, Orn32(N-C(O)-(CH2)14-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:44);および
実施例42: [A5c11, Orn33(N-C(O)-(CH2)14-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:45)。
Preferred compounds of formula (I) are:
Example 1: (A5c 11, 41 ) hGIP (1-42) -OH (SEQ ID NO: 4);
Example 2: (A5c 11, 40 ) hGIP (1-42) -OH (SEQ ID NO: 5);
Example 3: (A5c 11 , His 43 ) hGIP (1-43) -OH (SEQ ID NO: 6);
Example 4: (A5c 11, Asn 43 ) hGIP (1-43) -OH (SEQ ID NO: 7);
Example 5: (Aib 13 , Asp 43 ) hGIP (1-43) -NH 2 (SEQ ID NO: 8);
Example 6: (Aib 13 , Nle 14 , A5c 40 ) hGIP (1-42) -OH (SEQ ID NO: 9);
Example 7: (Aib 13 , A5c 40 ) hGIP (1-42) -OH (SEQ ID NO: 10);
Example 8: (A5c 11 , Ala 43 ) hGIP (1-43) -OH (SEQ ID NO: 11);
Example 9: (Aib 13 , Nle 14 , Phe 43 ) hGIP (1-43) -OH (SEQ ID NO: 12);
Example 10: (A5c 11 , Thr 43 ) hGIP (1-43) -OH (SEQ ID NO: 13);
Example 11: (A6c 11, 14, 41 ) hGIP (1-42) -OH (SEQ ID NO: 14);
Example 12: (Aib 13 , Trp 43 ) hGIP (1-43) -OH (SEQ ID NO: 15);
Example 13: (A5c 11, Ado 43 ) hGIP (1-43) -OH (SEQ ID NO: 16);
Example 14: (A6c 11, 14, 40 ) hGIP (1-42) -OH (SEQ ID NO: 17);
Example 15: [A6c 7, Cys ( Psu) 42] hGIP (1-42) -OH (SEQ ID NO: 18);
Example 16: (A6c 7, 41 ) hGIP (1-42) -OH (SEQ ID NO: 19);
Example 17: (A6c 7, 41 , Nle 14 ) hGIP (1-42) -OH (SEQ ID NO: 20);
Example 18: [A6c 7, Orn 35 (NC (O) - (CH 2) 12 -CH 3)] hGIP (1-42) -OH (SEQ ID NO: 21);
Example 19: [A6c 7, Orn 31 (NC (O) - (CH 2) 12 -CH 3)] hGIP (1-42) -OH (SEQ ID NO: 22);
Example 20: (A5c 11, 14, His 43) hGIP (1-43) -OH (SEQ ID NO: 23);
Example 21: (A5c 11, Nle 14 , His 43) hGIP (1-43) -OH (SEQ ID NO: 24);
Example 22: [A5c 11, Orn 32 (NC (O) - (CH 2) 14 -CH 3), His 43] hGIP (1-43) -OH (SEQ ID NO: 25);
Example 23: [A5c 11, Orn 33 (NC (O) - (CH 2) 14 -CH 3), His 43] hGIP (1-43) -OH (SEQ ID NO: 26);
Example 24: [A5c 11, Orn 43 (NC (O) - (CH 2) 14 -CH 3)] hGIP (1-43) -OH (SEQ ID NO: 27);
Example 25: [A5c 11 , Cys 32 (succinimide-N— (CH 2 ) 15 —CH 3 ), His 43 ] hGIP (1-43) -OH
(SEQ ID NO: 28);
Example 26: [A5c 11 , Cys 33 (succinimide-N— (CH 2 ) 15 —CH 3 ), His 43 ] hGIP (1-43) -OH
(SEQ ID NO: 29);
Example 27: [A5c 11 , Cys 43 (succinimide-N— (CH 2 ) 15 —CH 3 )] hGIP (1-43) —OH (SEQ ID NO: 30);
Example 28: (A5c 11 ) hGIP (1-30) -NH 2 (SEQ ID NO: 31);
Example 29: (A5c 11 , His 31 ) hGIP (1-31) -NH 2 (SEQ ID NO: 32);
Example 30: (A5c 11, 14 ) hGIP (1-30) -NH 2 (SEQ ID NO: 33);
Example 31: (A5c 11, 41 , Cys 32 ) hGIP (1-42) -NH 2 (SEQ ID NO: 34);
Example 32: (A5c 11, 41 , Cys 33 ) hGIP (1-42) -NH 2 (SEQ ID NO: 35);
Example 33: (A5c 11, 41 , Cys 43 ) hGIP (1-43) -NH 2 (SEQ ID NO: 36);
Example 34: [A5c 11, Orn 32 (NC (O) - (CH 2) 10 -CH 3), His 43] hGIP (1-43) -OH (SEQ ID NO: 37);
Example 35: [A5c 11, Orn 33 (NC (O) - (CH 2) 10 -CH 3), His 43] hGIP (1-43) -OH (SEQ ID NO: 38);
Example 36: [A5c 11, Lys 43 (NC (O) - (CH 2) 10 -CH 3)] hGIP (1-43) -OH (SEQ ID NO: 39);
Example 37: [A5c 11 , Cys 32 (succinimide-N— (CH 2 ) 11 —CH 3 ), His 43 ] hGIP (1-43) -OH
(SEQ ID NO: 40);
Example 38: [A5c 11 , Cys 33 (succinimide-N— (CH 2 ) 11 —CH 3 ), His 43 ] hGIP (1-43) -OH
(SEQ ID NO: 41);
Example 39: [A5c 11, Cys 43 ( succinimide -N- (CH 2) 11 -CH 3 )] hGIP (1-43) -OH (SEQ ID NO: 42);
Example 40: [A5c 11, Lys 43 (NC (O) - (CH 2) 14 -CH 3)] hGIP (1-43) -OH (SEQ ID NO: 43);
Example 41: [A5c 11 , Orn 32 (NC (O) — (CH 2 ) 14 —CH 3 ), His 43 ] hGIP (1-43) —OH (SEQ ID NO: 44); and Example 42: [A5c 11 , Orn 33 (NC (O)-(CH 2 ) 14 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 45).
本発明の別の観点によると、上記で要約された、および添付された特許請求の範囲において主張される、本発明に従う化合物は、さらに共有結合的に連結されたPEG部分を含んでいてよく、ここで前記PEG部分はその化合物にCys(マレイミド)、hCys(マレイミド)、またはPen(マレイミド)リンカーを介して連結されてCys(スクシンイミド-N-PEG)、hCys(スクシンイミド-N-PEG)、またはPen(スクシンイミド-N-PEG)を形成しており、ここで“スクシンイミド-N-PEG”は以下で定義されるように直鎖状または分枝状のどちらかである。そのPEG部分は約2,000から約80,000までの平均分子量を有し、好ましくはそのPEG部分は5K PEG、10K PEG、20K PEG、30K PEG、40K PEG、50K PEG、および60K
PEGからなるグループから選択されてCys(スクシンイミド-N-5K PEG)、Cys(スクシンイミド-N-10K PEG)、Cys(スクシンイミド-N-20K PEG)、Cys(スクシンイミド-N-30K PEG)、Cys(スクシンイミド-N-40K PEG)、Cys(スクシンイミド-N-50K PEG)、Cys(スクシンイミド-N-60K PEG)、hCys(スクシンイミド-N-5K PEG)、hCys(スクシンイミド-N-10K PEG)、hCys(スクシンイミド-N-20K PEG)、hCys(スクシンイミド-N-30K PEG)、hCys(スクシンイミド-N-40K PEG)、hCys(スクシンイミド-N-50K PEG)、hCys(スクシンイミド-N-60K PEG)、Pen(ス
クシンイミド-N-5K PEG)、Pen(スクシンイミド-N-10K PEG)、Pen(スクシンイミド-N-20K PEG)、Pen(スクシンイミド-N-30K PEG)、Pen(スクシンイミド-N-40K PEG)、Pen(スクシンイミド-N-50K PEG)、またはPen(スクシンイミド-N-60K PEG)を形成している。
According to another aspect of the invention, the compounds according to the invention as summarized above and claimed in the appended claims may further comprise a covalently linked PEG moiety, Wherein the PEG moiety is linked to the compound via a Cys (maleimide), hCys (maleimide), or Pen (maleimide) linker to form Cys (succinimide-N-PEG), hCys (succinimide-N-PEG), or Forms Pen (succinimide-N-PEG), where “succinimide-N-PEG” is either linear or branched as defined below. The PEG moiety has an average molecular weight of about 2,000 to about 80,000, preferably the PEG moiety is 5K PEG, 10K PEG, 20K PEG, 30K PEG, 40K PEG, 50K PEG, and 60K.
Cys (succinimide-N-5K PEG), Cys (succinimide-N-10K PEG), Cys (succinimide-N-20K PEG), Cys (succinimide-N-30K PEG), Cys (selected from the group consisting of PEG Succinimide-N-40K PEG), Cys (succinimide-N-50K PEG), Cys (succinimide-N-60K PEG), hCys (succinimide-N-5K PEG), hCys (succinimide-N-10K PEG), hCys ( Succinimide-N-20K PEG), hCys (succinimide-N-30K PEG), hCys (succinimide-N-50K PEG), hCys (succinimide-N-50K PEG), hCys (succinimide-N-60K PEG), Pen ( Succinimide-N-5K PEG), Pen (succinimide-N-20K PEG), Pen (succinimide-N-30K PEG), Pen (succinimide-N-30K PEG), Pen (succinimide-N-40K PEG), Pen ( Succinimide-N-50K PEG) or Pen (succinimide-N-60K PEG).
PEG化は16、30および31〜43位のアミノ酸残基のいずれか1個において、好ましくは32、33および43位のアミノ酸残基のいずれか1個において起こり、それによりCys(スクシンイミド-N-PEG)、hCys(スクシンイミド-N-PEG)、またはPen(スクシンイ
ミド-N-PEG)がそのアミノ酸残基の位置のいずれか1箇所に配置される。
PEGylation occurs at any one of the amino acid residues at positions 16, 30, and 31-43, preferably at any one of the amino acid residues at positions 32, 33, and 43, whereby Cys (succinimide-N— PEG), hCys (succinimide-N-PEG), or Pen (succinimide-N-PEG) is placed at any one of its amino acid residue positions.
さらに、上記の式(I)は、A44〜A47の位置にPEG化部位を提供するように拡張されてよい。本発明のそのようなPEG化された化合物のC末端はアミド化されていてよく、例えば(A5c11,41)hGIP(1-42)-NH2 (SEQ ID NO:68)であり、またはそれは遊離酸のままで
あってよく、例えば(A5c11,41)hGIP(1-42)-OH (SEQ ID NO:4)である。
Furthermore, the above formula (I) may be extended to provide a PEG sites on the position of A 44 to A 47. The C-terminus of such PEGylated compounds of the present invention may be amidated, for example (A5c 11 , 41) hGIP (1-42) -NH 2 (SEQ ID NO: 68), or it may be It may remain in the free acid, e.g., (A5c 11,41) hGIP (1-42) -OH: a (SEQ ID NO 4).
そのようなPEG化された化合物の好ましい化合物は次のものである:
実施例43: [A5c11, 41, Cys32(スクシンイミド-N-20K PEG)]hGIP(1-42)-NH2 (SEQ ID NO:46);
実施例44: [A5c11, 41, Cys33(スクシンイミド-N-20K PEG)]hGIP(1-42)-NH2 (SEQ ID NO:47);
実施例45: [A5c11, 41, Cys43(スクシンイミド-N-20K PEG)]hGIP(1-43)-NH2 (SEQ ID NO:48);
実施例46: [A5c11, 41, Cys43(スクシンイミド-N-30K PEG)]hGIP(1-43)-NH2 (SEQ ID NO:49);
実施例47: [A5c11, Nle14, Cys43(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-20K PEG)]hGIP(1-43)-NH2 (SEQ ID NO:50);
実施例48: [A5c11, Nle14, Cys32(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-20K PEG)]hGIP(1-42)-NH2 (SEQ ID NO:51);
実施例49: [A5c11, Nle14, Cys33(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-20K PEG)]hGIP(1-42)-NH2 (SEQ ID NO:52);
実施例50: [A5c11, Cys43(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-43)-NH2(SEQ ID NO:53);
実施例51: [A5c11, Cys32(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:54);
実施例52: [A5c11, Cys33(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:55);
実施例53: [A5c11, Nle14, Cys43(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-43)-NH2 (SEQ ID NO:56);
実施例54: [A5c11, Nle14, Cys32(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-42)-NH2 (SEQ ID NO:57);
実施例55: [A5c11, Nle14, Cys33(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-42)-NH2 (SEQ ID NO:58);
実施例56: [A5c11, Cys43(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K
PEG)-CH2-20K PEG)]hGIP(1-43)-NH2 (SEQ ID NO:59);
実施例57: [A5c11, Cys32(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K
PEG)-CH2-20K PEG)]hGIP(1-42)-NH2 (SEQ ID NO:60);
実施例58: [A5c11, Cys33(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K
PEG)-CH2-20K PEG)]hGIP(1-42)-NH2 (SEQ ID NO:61);
実施例59: [A5c11, 14, Cys43(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-43)-NH2(SEQ ID NO:62);
実施例60: [A5c11, 14, Cys32(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:63);
実施例61: [A5c11, 14, Cys33(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-20K-PEG)]hGIP(1-42)-NH2(SEQ ID NO:64);
実施例62: [A5c11, 14, Cys43(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-43)-NH2 (SEQ ID NO:65);
実施例63: [A5c11, 14, Cys32(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-42)-NH2 (SEQ ID NO:66);および
実施例64: [A5c11, 14, Cys33(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(20K PEG)-CH2-20K PEG)]hGIP(1-42)-NH2 (SEQ ID NO:67)。
Preferred compounds for such PEGylated compounds are:
Example 43: [A5c 11, 41 , Cys 32 (succinimide-N-20K PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 46);
Example 44: [A5c 11, 41 , Cys 33 (succinimide-N-20K PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 47);
Example 45: [A5c 11, 41 , Cys 43 (succinimide-N-20K PEG)] hGIP (1-43) -NH 2 (SEQ ID NO: 48);
Example 46: [A5c 11, 41 , Cys 43 (succinimide-N-30K PEG)] hGIP (1-43) -NH 2 (SEQ ID NO: 49);
Example 47: [A5c 11, Nle 14 , Cys 43 ( succinimide -N- (CH 2) 2 -C ( O) NH- (CH 2) 3 -20K PEG)] hGIP (1-43) -NH 2 ( SEQ ID NO: 50);
Example 48: [A5c 11, Nle 14 , Cys 32 ( succinimide -N- (CH 2) 2 -C ( O) NH- (CH 2) 3 -20K PEG)] hGIP (1-42) -NH 2 ( SEQ ID NO: 51);
Example 49: [A5c 11, Nle 14 , Cys 33 ( succinimide -N- (CH 2) 2 -C ( O) NH- (CH 2) 3 -20K PEG)] hGIP (1-42) -NH 2 ( SEQ ID NO: 52);
Example 50: [A5c 11, Cys 43 ( succinimide -N- (CH 2) 2 -C ( O) NH- (CH 2) 3 -20K-PEG)] hGIP (1-43) -NH 2 (SEQ ID NO: 53);
Example 51: [A5c 11, Cys 32 ( succinimide -N- (CH 2) 2 -C ( O) NH- (CH 2) 3 -20K-PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 54);
Example 52: [A5c 11, Cys 33 ( succinimide -N- (CH 2) 2 -C ( O) NH- (CH 2) 3 -20K-PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 55);
Example 53: [A5c 11 , Nle 14 , Cys 43 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 —O—CH 2 —CH (20K PEG) —CH 2 — 20K PEG)] hGIP (1-43) -NH 2 (SEQ ID NO: 56);
Example 54: [A5c 11 , Nle 14 , Cys 32 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 —O—CH 2 —CH (20K PEG) —CH 2 — 20K PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 57);
Example 55: [A5c 11 , Nle 14 , Cys 33 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 —O—CH 2 —CH (20K PEG) —CH 2 — 20K PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 58);
Example 56: [A5c 11 , Cys 43 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 —O—CH 2 —CH (20K
PEG) -CH 2 -20K PEG)] hGIP (1-43) -NH 2 (SEQ ID NO: 59);
Example 57: [A5c 11 , Cys 32 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 —O—CH 2 —CH (20K
PEG) -CH 2 -20K PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 60);
Example 58: [A5c 11 , Cys 33 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 —O—CH 2 —CH (20K
PEG) -CH 2 -20K PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 61);
Example 59: [A5c 11, 14 , Cys 43 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 -20K-PEG)] hGIP (1-43) -NH 2 ( SEQ ID NO: 62);
Example 60: [A5c 11, 14 , Cys 32 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 -20K-PEG)] hGIP (1-42) -NH 2 ( SEQ ID NO: 63);
Example 61: [A5c 11, 14 , Cys 33 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 -20K-PEG)] hGIP (1-42) -NH 2 ( SEQ ID NO: 64);
Example 62: [A5c 11, 14 , Cys 43 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 —O—CH 2 —CH (20K PEG) —CH 2 -20K PEG)] hGIP (1-43) -NH 2 (SEQ ID NO: 65);
Example 63: [A5c 11, 14 , Cys 32 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 —O—CH 2 —CH (20K PEG) —CH 2 -20K PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 66); and Example 64: [A5c 11, 14 , Cys 33 (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2) 3 -O-CH 2 -CH (20K PEG) -CH 2 -20K PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 67).
本出願は、下記の一般的に理解されている略語を用いる:
Abu: α-アミノ酪酸
Acc: 1-アミノ-1-シクロ(C3-C9)アルキルカルボン酸
A3c: 1-アミノ-1-シクロプロパンカルボン酸
A4c: 1-アミノ-1-シクロブタンカルボン酸
A5c: 1-アミノ-1-シクロペンタンカルボン酸
A6c: 1-アミノ-1-シクロヘキサンカルボン酸
Act: 4-アミノ-4-カルボキシテトラヒドロピラン
Ado: 12-アミノドデカン酸
Aib: α-アミノイソ酪酸
Aic: 2-アミノインダン-2-カルボン酸
AlaまたはA: アラニン
β-Ala: ベータ-アラニン
Amp: 4-アミノ-フェニルアラニン;
Apc: 4-アミノ-4-カルボキシピペリジン:
ArgまたはR: アルギニン
hArg: ホモアルギニン
AsnまたはN: アスパラギン
AspまたはD: アスパラギン酸
Aun: 11-アミノウンデカン酸
Ava: 5-アミノ吉草酸
Cha: β-シクロヘキシルアラニン
CysまたはC: システイン
Dhp: 3,4-デヒドロプロリン
Dmt: 5,5-ジメチルチアゾリジン-4-カルボン酸
Gaba: γ-アミノ酪酸
GlnまたはQ: グルタミン
GluまたはE: グルタミン酸
GlyまたはG: グリシン
HisまたはH: ヒスチジン
4Hppa: 3-(4-ヒドロキシフェニル)プロピオン酸
3Hyp: 3-ヒドロキシプロリン
4Hyp: 4-ヒドロキシプロリン
hPro: ホモプロリン
IleまたはI: イソロイシン
4Ktp: 4-ケトプロリン
LeuまたはL: ロイシン
LysまたはK: リシン
MetまたはM: メチオニン
Nle: ノルロイシン
NMe-Tyr: N-メチル-チロシン
1Nalまたは1-Nal: β-(1-ナチフル)アラニン
2Nalまたは2-Nal: β-(2-ナチフル)アラニン
Nle: ノルロイシン
Nva: ノルバリン
Orn: オルニチン
2Palまたは2-Pal: β-(2-ピリジニル)アラニン
3Palまたは3-Pal: β-(3-ピリジニル)アラニン
4Palまたは4-Pal: β-(4-ピリジニル)アラニン
Pen: ペニシラミン
PheまたはF: フェニルアラニン
(3,4,5F)Phe: 3,4,5-トリフルオロフェニルアラニン
(2,3,4,5,6)Phe: 2,3,4,5,6-ペンタフルオロフェニルアラニン
ProまたはP: プロリン
Psu: N-プロピルスクシンイミド
SerまたはS: セリン
Taz: β-(4-チアゾリル)アラニン
3Thi: β-(3-チエニル)アラニン
ThrまたはT: スレオニン
Thz: チオプロリン
Tic: テトラヒドロイソキノリン-3-カルボン酸
Tle: tert-ロイシン
TrpまたはW: トリプトファン
TyrまたはY: チロシン
ValまたはV: バリン。
This application uses the following commonly understood abbreviations:
Abu: α-aminobutyric acid
Acc: 1-amino-1-cyclo (C 3 -C 9 ) alkylcarboxylic acid
A3c: 1-amino-1-cyclopropanecarboxylic acid
A4c: 1-amino-1-cyclobutanecarboxylic acid
A5c: 1-amino-1-cyclopentanecarboxylic acid
A6c: 1-amino-1-cyclohexanecarboxylic acid
Act: 4-amino-4-carboxytetrahydropyran
Ado: 12-aminododecanoic acid
Aib: α-aminoisobutyric acid
Aic: 2-Aminoindan-2-carboxylic acid
Ala or A: alanine β-Ala: beta-alanine
Amp: 4-amino-phenylalanine;
Apc: 4-amino-4-carboxypiperidine:
Arg or R: Arginine
hArg: Homoarginine
Asn or N: Asparagine
Asp or D: Aspartic acid
Aun: 11-aminoundecanoic acid
Ava: 5-aminovaleric acid
Cha: β-Cyclohexylalanine
Cys or C: Cysteine
Dhp: 3,4-dehydroproline
Dmt: 5,5-dimethylthiazolidine-4-carboxylic acid
Gaba: γ-aminobutyric acid
Gln or Q: Glutamine
Glu or E: Glutamic acid
Gly or G: Glycine
His or H: Histidine
4Hppa: 3- (4-hydroxyphenyl) propionic acid
3Hyp: 3-hydroxyproline
4Hyp: 4-hydroxyproline
hPro: Homoproline
Ile or I: Isoleucine
4Ktp: 4-ketoproline
Leu or L: Leucine
Lys or K: Lysine
Met or M: Methionine
Nle: Norleucine
NMe-Tyr: N-methyl-tyrosine
1Nal or 1-Nal: β- (1-Natiflu) alanine
2Nal or 2-Nal: β- (2-Nachiflu) alanine
Nle: Norleucine
Nva: Norvaline
Orn: Ornithine
2Pal or 2-Pal: β- (2-pyridinyl) alanine
3Pal or 3-Pal: β- (3-pyridinyl) alanine
4Pal or 4-Pal: β- (4-pyridinyl) alanine
Pen: Penicillamine
Phe or F: Phenylalanine
(3,4,5F) Phe: 3,4,5-trifluorophenylalanine
(2,3,4,5,6) Phe: 2,3,4,5,6-pentafluorophenylalanine
Pro or P: Proline
Psu: N-propyl succinimide
Ser or S: Serine
Taz: β- (4-thiazolyl) alanine
3Thi: β- (3-thienyl) alanine
Thr or T: Threonine
Thz: Thioproline
Tic: Tetrahydroisoquinoline-3-carboxylic acid
Tle: tert-leucine
Trp or W: Tryptophan
Tyr or Y: tyrosine
Val or V: Valine.
本明細書において用いられる特定の他の略語を次のように定義する:
Act: アセトニトリル
Boc: tert-ブチルオキシカルボニル
BSA: ウシ血清アルブミン
DCM: ジクロロメタン
DIPEA: ジイソプロピルエチルアミン
DMF: ジメチルホルムアミド
DTT: ジチオスレイトール(dithiothrieitol)
ESI: エレクトロスプレーイオン化
Fmoc: 9-フルオレニルメチルオキシカルボニル
HBTU: 2-(1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスフェート
HOBT: 1-ヒドロキシベンゾトリアゾール
HPLC: 高速液体クロマトグラフィー
IBMX: イソブチルメチルキサンチン
LC-MS: 液体クロマトグラフィー−質量分析
Mtt: メチルトリチル
NMP: N-メチルピロリドン
5K PEG: ポリエチレングリコールであって、他の官能基または部分、例えばリンカー
を含んでいてよく、下記で定義されるように直鎖状または分枝状のどちらかであり、約5,000の平均総分子量を有するポリエチレングリコール
10K PEG: ポリエチレングリコールであって、他の官能基または部分、例えばリンカーを含んでいてよく、下記で定義されるように直鎖状または分枝状のどちらかであり、約10,000の平均総分子量を有するポリエチレングリコール
20K PEG: ポリエチレングリコールであって、他の官能基または部分、例えばリンカーを含んでいてよく、下記で定義されるように直鎖状または分枝状のどちらかであり、約20,000の平均総分子量を有するポリエチレングリコール
30K PEG: ポリエチレングリコールであって、他の官能基または部分、例えばリンカーを含んでいてよく、下記で定義されるように直鎖状または分枝状のどちらかであり、約30,000の平均総分子量を有するポリエチレングリコール
40K PEG: ポリエチレングリコールであって、他の官能基または部分、例えばリンカーを含んでいてよく、下記で定義されるように直鎖状または分枝状のどちらかであり、約40,000の平均総分子量を有するポリエチレングリコール
50K PEG: ポリエチレングリコールであって、他の官能基または部分、例えばリンカーを含んでいてよく、下記で定義されるように直鎖状または分枝状のどちらかであり、約50,000の平均総分子量を有するポリエチレングリコール
60K PEG: ポリエチレングリコールであって、他の官能基または部分、例えばリンカーを含んでいてよく、下記で定義されるように直鎖状または分枝状のどちらかであり、約60,000の平均総分子量を有するポリエチレングリコール
tBu: tert-ブチル
TIS: トリイソプロピルシラン
Trt: トリチル
TFA: トリフルオロ酢酸
Z: ベンジルオキシカルボニル
“Cys(スクシンイミド-N-アルキル)”は次の構造を有する:
Certain other abbreviations used herein are defined as follows:
Act: Acetonitrile
Boc: tert-butyloxycarbonyl
BSA: Bovine serum albumin
DCM: dichloromethane
DIPEA: Diisopropylethylamine
DMF: Dimethylformamide
DTT: dithiothrieitol
ESI: Electrospray ionization
Fmoc: 9-fluorenylmethyloxycarbonyl
HBTU: 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
HOBT: 1-hydroxybenzotriazole
HPLC: High performance liquid chromatography
IBMX: Isobutylmethylxanthine
LC-MS: Liquid chromatography-mass spectrometry
Mtt: Methyltrityl
NMP: N-methylpyrrolidone
5K PEG: Polyethylene glycol, which may contain other functional groups or moieties such as linkers, either linear or branched as defined below, with an average of about 5,000 Polyethylene glycol with total molecular weight
10K PEG: Polyethylene glycol, which may contain other functional groups or moieties such as linkers, either linear or branched as defined below, with an average of about 10,000 Polyethylene glycol with total molecular weight
20K PEG: Polyethylene glycol, which may contain other functional groups or moieties such as linkers, either linear or branched as defined below, with an average of about 20,000 Polyethylene glycol with total molecular weight
30K PEG: Polyethylene glycol, which may contain other functional groups or moieties such as linkers, either linear or branched as defined below, with an average of about 30,000 Polyethylene glycol with total molecular weight
40K PEG: Polyethylene glycol, which may contain other functional groups or moieties such as linkers, either linear or branched as defined below, with an average of about 40,000 Polyethylene glycol with total molecular weight
50K PEG: Polyethylene glycol, which may contain other functional groups or moieties such as linkers, either linear or branched as defined below, with an average of about 50,000 Polyethylene glycol with total molecular weight
60K PEG: Polyethylene glycol, which may contain other functional groups or moieties such as linkers, either linear or branched as defined below, with an average of about 60,000 Polyethylene glycol with total molecular weight
tBu: tert-butyl
TIS: Triisopropylsilane
Trt: Trityl
TFA: trifluoroacetic acid
Z: Benzyloxycarbonyl “Cys (succinimide-N-alkyl)” has the following structure:
“Cys(Psu)”は次の構造を有する: “Cys (Psu)” has the following structure:
“Orn(N-C(O)-(CH2)12-CH3)”は次の構造を有する: “Orn (NC (O) — (CH 2 ) 12 —CH 3 )” has the following structure:
“Cys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)”は次の構造を有し: “Cys (succinimide-N— (CH 2 ) x —C (O) —NH— (CH 2 ) y —CH 3 )” has the following structure:
ここで、x = 1〜30、およびy = 1〜30である。 Here, x = 1 to 30 and y = 1 to 30.
“hCys(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)”は次の構造を有し: “HCys (succinimide-N— (CH 2 ) x —C (O) —NH— (CH 2 ) y —CH 3 )” has the following structure:
ここで、x = 1〜30、およびy = 1〜30である。 Here, x = 1 to 30 and y = 1 to 30.
“Pen(スクシンイミド-N-(CH2)x-C(O)-NH-(CH2)y-CH3)”は次の構造を有し: “Pen (succinimide-N— (CH 2 ) x —C (O) —NH— (CH 2 ) y —CH 3 )” has the following structure:
ここで、x = 1〜30、およびy = 1〜30である。 Here, x = 1 to 30 and y = 1 to 30.
“Cys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)”は次の構造を有し: “Cys (succinimide-N— (CH 2 ) s —NH—C (O) — (CH 2 ) t —CH 3 )” has the following structure:
ここで、s = 1〜30、およびt = 1〜30である。 Here, s = 1 to 30 and t = 1 to 30.
“hCys(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)”は次の構造を有し: “HCys (succinimide-N— (CH 2 ) s —NH—C (O) — (CH 2 ) t —CH 3 )” has the following structure:
ここで、s = 1〜30、およびt = 1〜30である。 Here, s = 1 to 30 and t = 1 to 30.
“Pen(スクシンイミド-N-(CH2)s-NH-C(O)-(CH2)t-CH3)”は次の構造を有し: “Pen (succinimide-N— (CH 2 ) s —NH—C (O) — (CH 2 ) t —CH 3 )” has the following structure:
ここで、s = 1〜30、およびt = 1〜30である。 Here, s = 1 to 30 and t = 1 to 30.
“Cys(スクシンイミド-N-PEG)”は次の構造を有する: “Cys (succinimide-N-PEG)” has the following structure:
“hCys(スクシンイミド-N-PEG)”は次の構造を有する: “HCys (succinimide-N-PEG)” has the following structure:
“Pen(スクシンイミド-N-PEG)”は次の構造を有する: “Pen (succinimide-N-PEG)” has the following structure:
“Cys(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-PEG)”は次の構造を有する: “Cys (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 -PEG)” has the following structure:
“Cys(スクシンイミド-N-(CH2)2-C(O)NH-(CH2)3-O-CH2-CH(PEG)-CH2-PEG)”は次の構造を有する: “Cys (succinimide-N— (CH 2 ) 2 —C (O) NH— (CH 2 ) 3 —O—CH 2 —CH (PEG) —CH 2 -PEG)” has the following structure:
N末端のアミノ酸を除いて、この開示における全てのアミノ酸の略語(例えばAla)は-NH-CI(R’)-CO-の構造を表しており、ここでRおよびR’はそれぞれ独立して水素またはアミノ酸の側鎖(例えば、Alaに関してはR = CH3およびR’ = H)であり、またはRおよびR
’は繋がれて環系を形成していてよい。N末端アミノ酸に関しては、その略語は(R2R3)N-CI(R’)-CO-の構造を表し、ここでR2およびR3は上記の式(I)で定義されたものである
。
Except for the N-terminal amino acid, all amino acid abbreviations in this disclosure (eg, Ala) represent the structure of —NH—CI (R ′) — CO—, where R and R ′ are each independently Is a hydrogen or amino acid side chain (eg, R = CH 3 and R ′ = H for Ala), or R and R
'May be connected to form a ring system. For the N-terminal amino acid, the abbreviation represents the structure of (R 2 R 3 ) N—CI (R ′) — CO—, where R 2 and R 3 are as defined in formula (I) above. is there.
用語“(C1-C30)炭化水素部分”は、アルキル、アルケニルおよびアルキニルを含み、アルケニルおよびアルキニルの場合ではC2-C30がある。 The term “(C 1 -C 30 ) hydrocarbon moiety” includes alkyl, alkenyl and alkynyl, and in the case of alkenyl and alkynyl there is C 2 -C 30 .
この発明のペプチドは、本明細書において別の形式、例えば(A5c2)hGIP(1-42)-OH (SEQ
ID NO:3)によっても表され、それはカッコの間に置かれた天然の配列から置換されたア
ミノ酸(例えば、hGIP中のAla2の代わりにA5c2)を有する。カッコの間の数字は、そのペプチド中に存在するアミノ酸の番号を表す(例えば、hGIP(1-42)-OH (SEQ ID NO:1)はhGIPに関するペプチド配列のアミノ酸1〜42である)。hGIP(1-30)-NH2 (SEQ ID NO:2)中
の名称“NH2”は、そのペプチドのC末端がアミド化されていることを示し;hGIP(1-42) (SEQ ID NO:1)またはhGIP(1-42)-OH (SEQ ID NO:1)はC末端が遊離酸であることを意味する。
The peptides of this invention may be expressed in other forms herein, such as (A5c 2 ) hGIP (1-42) -OH (SEQ
It is also represented by ID NO: 3), which has an amino acid substituted from the natural sequence placed between the brackets (eg A5c 2 instead of Ala 2 in hGIP). The number between the brackets represents the number of the amino acid present in the peptide (eg hGIP (1-42) -OH (SEQ ID NO: 1) is amino acids 1-42 of the peptide sequence for hGIP). The name “NH 2 ” in hGIP (1-30) -NH 2 (SEQ ID NO: 2) indicates that the C-terminus of the peptide is amidated; hGIP (1-42) (SEQ ID NO: 2 : 1) or hGIP (1-42) -OH (SEQ ID NO: 1) means that the C-terminus is a free acid.
ヒトのGIP(“hGIP”)は次のアミノ酸配列を有する: Human GIP (“hGIP”) has the following amino acid sequence:
“アシル”は、R’’-C(O)-を指し、ここでR’’はH、アルキル、置換されたアルキル
、ヘテロアルキル、置換されたヘテロアルキル、アルケニル、置換されたアルケニル、アリール、アルキルアリール、または置換されたアルキルアリールである。
“Acyl” refers to R ″ —C (O) —, where R ″ is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, Alkylaryl or substituted alkylaryl.
“アルキル”は1個以上の炭素原子を含む炭化水素基を指し、ここで多数の炭素原子は、もし存在するならば、単結合によりつながっている。アルキル炭化水素基は直鎖であってよく、または1個以上の分枝または環式基を含んでいてよい。 “Alkyl” refers to a hydrocarbon group containing one or more carbon atoms, where multiple carbon atoms, if present, are joined by single bonds. The alkyl hydrocarbon group may be straight-chain or may contain one or more branched or cyclic groups.
“置換されたアルキル”は、炭化水素基の1個以上の水素原子が、ハロゲン(すなわちフッ素、塩素、臭素およびヨウ素)、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、ハロゲンで
置換された-C1-20アルキル、-CF3、-OCH3、-OCF3、および-(CH2)0-20-COOHからなるグル
ープから選択される1個以上の置換基で置き換えられているアルキルを指す。異なる態様において、1、2、3または4個の置換基が存在する。-(CH2)0-20-COOHの存在は、結果
としてアルキル酸の生成をもたらす。-(CH2)0-20-COOHを含む、またはそれで構成される
アルキル酸の例には、2-ノルボルナン酢酸、tert-酪酸および3-シクロペンチルプロピオ
ン酸が含まれる。
“Substituted alkyl” means that one or more hydrogen atoms of a hydrocarbon group are halogen (ie, fluorine, chlorine, bromine and iodine), —OH, —CN, —SH, —NH 2 , —NHCH 3 , — One or more substitutions selected from the group consisting of NO 2 , —C 1-20 alkyl substituted with halogen, —CF 3 , —OCH 3 , —OCF 3 , and — (CH 2 ) 0-20 —COOH Refers to alkyl substituted with a group. In different embodiments, there are 1, 2, 3 or 4 substituents. The presence of- (CH 2 ) 0-20 -COOH results in the formation of alkyl acids. Examples of alkyl acids comprising or consisting of — (CH 2 ) 0-20 —COOH include 2-norbornane acetic acid, tert-butyric acid and 3-cyclopentylpropionic acid.
“ヘテロアルキル”は、炭化水素基中の炭素原子の1個以上が次の基:アミノ、アミド、-O-、-S-、またはカルボニルの内の1個以上で置き換えられているアルキルを指す。異なる態様において、1または2個のヘテロ原子が存在する。 “Heteroalkyl” refers to an alkyl in which one or more of the carbon atoms in the hydrocarbon group is replaced by one or more of the following groups: amino, amide, —O—, —S—, or carbonyl. . In different embodiments, there are 1 or 2 heteroatoms.
“置換されたヘテロアルキル”は、炭化水素基の1個以上の水素原子が、ハロゲン、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、ハロゲンで置換された-C1-20アルキル、-CF3、-OCH3、-OCF3、および-(CH2)0-20-COOHからなるグループから選択される1個以上の置換基で置き換えられているヘテロアルキルを指す。異なる態様において、1、2、3または4個の置換基が存在する。 “Substituted heteroalkyl” is a group in which one or more hydrogen atoms of a hydrocarbon group are substituted with halogen, —OH, —CN, —SH, —NH 2 , —NHCH 3 , —NO 2 , or halogen— A heteroalkyl substituted with one or more substituents selected from the group consisting of C 1-20 alkyl, —CF 3 , —OCH 3 , —OCF 3 , and — (CH 2 ) 0-20 —COOH; Point to. In different embodiments, there are 1, 2, 3 or 4 substituents.
“アルケニル”は、2個以上の炭素で構成され、1個以上の炭素−炭素二重結合が存在する炭化水素基を指す。アルケニル炭化水素基は直鎖であってよく、または1個以上の分枝または環式基を含んでいてよい。 “Alkenyl” refers to a hydrocarbon group composed of two or more carbons and having one or more carbon-carbon double bonds. An alkenyl hydrocarbon group may be straight-chain or contain one or more branched or cyclic groups.
“置換されたアルケニル”は、1個以上の水素がハロゲン、-OH、-CN、-SH、-NH2、-NHCH3、-NO2、ハロゲンで置換された-C1-20アルキル、-CF3、-OCH3、-OCF3、および-(CH2)0-20-COOHからなるグループから選択される1個以上の置換基で置き換えられているアルケニルを指す。異なる態様において、1、2、3または4個の置換基が存在する。 “Substituted alkenyl” refers to —C 1-20 alkyl in which one or more hydrogens are replaced by halogen, —OH, —CN, —SH, —NH 2 , —NHCH 3 , —NO 2 , halogen, — Refers to alkenyl substituted with one or more substituents selected from the group consisting of CF 3 , —OCH 3 , —OCF 3 , and — (CH 2 ) 0-20 —COOH. In different embodiments, there are 1, 2, 3 or 4 substituents.
“アリール”は、共役パイ電子系を有する少なくとも1個の環を有し、3個までの共役した、または縮合した環系を含む、場合により置換された芳香族基を指す。アリールには炭素環式アリール、ヘテロ環式アリールおよびビアリール基が含まれる。好ましくは、アリールは5または6員環である。ヘテロ環式アリールに関して好ましい原子は、1個以上の硫黄、酸素および/または窒素である。アリールの例には、フェニル、1-ナフチル、2-ナフチル、インドール、キノリン、2-イミダゾール、および9-アントラセンが含まれる。アリール置換基は、-C1-20アルキル、-C1-20アルコキシ、ハロゲン、-OH、-CN、-SH、-NH2、-NO2、ハロゲンで置換された-C1-20アルキル、-CF3、-OCF3、および-(CH2)0-20-COOH
からなるグループから選択される。異なる態様において、アリールは0、1、2、3または4個の置換基を含む。
“Aryl” refers to an optionally substituted aromatic group having at least one ring having a conjugated pi-electron system and including up to three conjugated or fused ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups. Preferably, aryl is a 5 or 6 membered ring. Preferred atoms for the heterocyclic aryl are one or more sulfur, oxygen and / or nitrogen. Examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, and 9-anthracene. Aryl substituents are -C 1-20 alkyl, -C 1-20 alkoxy, halogen, -OH, -CN, -SH, -NH 2 , -NO 2 , -C 1-20 alkyl substituted with halogen, -CF 3, -OCF 3, and - (CH 2) 0-20 -COOH
Selected from the group consisting of In different embodiments, aryl contains 0, 1, 2, 3 or 4 substituents.
“アルキルアリール”は“アリール”に結合した“アルキル”を指す。 “Alkylaryl” refers to “alkyl” bonded to “aryl”.
合成
この発明のペプチドは、標準的な固相ペプチド合成により調製することができる。例えば、Stewart, J. M., et al., 1984, Solid Phase Synthesis, Pierce Chemical Co., 第2版を参照。R1がNH-X2-CH2-CONH2、すなわち、Z0 = CONH2である場合、そのペプチドの
合成はRinkアミドMBHA樹脂にカップリングしたFmoc-HN-X2-CH2-CONH2を用いて出発する。R1がNH-X2-CH2-COOH、すなわち、Z0 = COOHである場合、そのペプチドの合成はWang樹脂
にカップリングしたFmoc-HN-X2-CH2-COOHを用いて出発する。この特定の工程に関して、
2モル当量のFmoc-HN-X2-COOH、HBTUおよびHOBtならびに10モル当量のDIPEAを用いる。
カップリングの時間は約8時間である。
Synthesis The peptides of this invention can be prepared by standard solid phase peptide synthesis. See, for example, Stewart, JM, et al., 1984, Solid Phase Synthesis, Pierce Chemical Co., 2nd edition. When R 1 is NH-X 2 -CH 2 -CONH 2 , that is, Z 0 = CONH 2 , the synthesis of the peptide is Fmoc-HN-X 2 -CH 2 -CONH 2 coupled to Rink amide MBHA resin Start with. When R 1 is NH—X 2 —CH 2 —COOH, ie, Z 0 = COOH, synthesis of the peptide starts with Fmoc-HN—X 2 —CH 2 —COOH coupled to Wang resin. . For this particular process,
Two molar equivalents of Fmoc-HN-X 2 —COOH, HBTU and HOBt and 10 molar equivalents of DIPEA are used.
The coupling time is about 8 hours.
A5c、A6c、および/またはAibを含むこの発明のGIPアナログの合成において、これ
らの残基およびそれらのすぐ後ろの残基に関するカップリング時間は2時間である。
In the synthesis of the GIP analogs of this invention comprising A5c, A6c, and / or Aib, the coupling time for these residues and the residues immediately following them is 2 hours.
上記の一般式の置換基R2およびR3は、N末端アミノ酸A1の遊離アミンに、当技術で既知の標準的な技法により結合させることができる。例えばアルキル基、例えば(C1-C30)アルキルは、還元的アルキル化を用いて結合させることができる。ヒドロキシアルキル基、例えば(C1-C30)ヒドロキシアルキルも還元的アルキル化を用いて結合させることができ、ここで遊離のヒドロキシル基はtert-ブチルエステルを用いて保護される。アシル基、例え
ば-C(O)X3は、完了した樹脂を塩化メチレン中で3モル当量の遊離酸およびジイソプロピ
ルカルボジイミド両方と約1時間混合することによる、遊離酸、例えば-X3COOHのN末端
アミノ酸の遊離アミンへのカップリングにより結合させることができる。3-フルオロ-4-
ヒドロキシフェニル酢酸のように遊離酸が遊離のヒドロキシル基を含む場合、カップリングは追加の3モル当量のHOBTと共に実施されるべきである。
The substituents R 2 and R 3 of the above general formula can be attached to the free amine of the N-terminal amino acid A 1 by standard techniques known in the art. For example, an alkyl group, such as (C 1 -C 30 ) alkyl, can be attached using reductive alkylation. Hydroxyalkyl groups such as (C 1 -C 30 ) hydroxyalkyl can also be attached using reductive alkylation, wherein the free hydroxyl group is protected with a tert-butyl ester. Acyl groups, such as —C (O) X 3 , can be obtained by mixing the completed resin in methylene chloride with 3 molar equivalents of both free acid and diisopropylcarbodiimide for about 1 hour, eg, N of free acid, eg, —X 3 COOH. It can be coupled by coupling the terminal amino acid to a free amine. 3-Fluoro-4-
If the free acid contains a free hydroxyl group, such as hydroxyphenylacetic acid, the coupling should be performed with an additional 3 molar equivalents of HOBT.
下記の実施例は、この発明のペプチドを作るための合成法を記述し、その方法は当業者には周知である。当業者には他の方法も知られている。実施例は説明のために提供されるのであって、本発明の範囲を限定することを意味するものでは決して無い。 The following examples describe synthetic methods for making the peptides of this invention, which methods are well known to those skilled in the art. Other methods are known to those skilled in the art. The examples are provided for illustrative purposes and are not meant to limit the scope of the invention in any way.
実施例15:[A6c 7 , Cys(Psu) 42 ]hGIP(1-42)-OH
Liberty Peptide Synthesizer (CEM;米国ノースキャロライナ州マシューズ)上で、0.1
mmoleスケールで、マイクロ波支援Fmoc化学を用いる固相ペプチド合成を用いてペプチドを組み立てた。プレロードされた(Pre-loaded)Fmoc-Cys(Trt)-Wang樹脂(0.59 mmole/g;Novabiochem,米国カリフォルニア州サンディエゴ)を用いてC末端酸ペプチド(C-terminal acid peptide)を生成した。その樹脂(0.17 g)を50 mlコニカルチューブの中に、15 mlのジメチルホルムアミド(DMF)と共に置き、合成機上の樹脂の位置に入れた。次いでその
樹脂を、自動化されたプロセスにより定量的に反応容器に移した。0.1 mmoleスケールで
の合成のための標準的なLiberty合成プロトコルを用いた。このプロトコルには、DMF中の0.1M N-ヒドロキシベンゾトリアゾール(HOBT)を含む20% ピペリジン7 mlを用いた最初の
処理によるN末端のFmoc部分の脱保護が含まれている。その最初の脱保護の工程は、マイクロ波電力(45ワット、最大温度75℃)および窒素による泡立て(3秒間オン/7秒間オフ)を用いて30秒間であった。次いで反応容器から液体を排出し(drained)、それ
が3分間の期間であること以外は第1の処理と同じである第2のピペリジン処理を行った。次いで樹脂から液体を排出し、DMFで数回、完全に洗浄した。次いでDMF中で0.2Mのストック溶液として調製した保護されたアミノ酸Fmoc-Thr(tBu)-OH(2.5 ml, 5当量)、続いて1.0 mlのDMF中0.45M (4.5当量) HBTU [2-(1H-ベンゾ-トリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスフェート]を添加した。これに続き0.5 mlのNMP
(N-メチルピロリジノン(N-methylpyrrollidinone))中2M (10当量) DIPEA (ジイソプロピルエチルアミン)を添加した。カップリングの工程は、20ワットのマイクロ波電力、7
5℃の最大温度、および同程度の窒素による泡立てを用いて5分間行った。
Example 15: [A6c 7, Cys ( Psu) 42] hGIP (1-42) -OH
0.1 on the Liberty Peptide Synthesizer (CEM; Matthews, North Carolina, USA)
Peptides were assembled using solid phase peptide synthesis using microwave assisted Fmoc chemistry on a mmole scale. C-terminal acid peptide was generated using pre-loaded Fmoc-Cys (Trt) -Wang resin (0.59 mmole / g; Novabiochem, San Diego, CA, USA). The resin (0.17 g) was placed in a 50 ml conical tube with 15 ml dimethylformamide (DMF) and placed in the resin position on the synthesizer. The resin was then quantitatively transferred to the reaction vessel by an automated process. A standard Liberty synthesis protocol for synthesis on the 0.1 mmole scale was used. This protocol includes deprotection of the N-terminal Fmoc moiety by initial treatment with 7 ml of 20% piperidine containing 0.1M N-hydroxybenzotriazole (HOBT) in DMF. The initial deprotection step was 30 seconds using microwave power (45 watts, maximum temperature 75 ° C.) and nitrogen bubbling (3 seconds on / 7 seconds off). The liquid was then drained from the reaction vessel and a second piperidine treatment was performed which was the same as the first treatment except that it was for a period of 3 minutes. The liquid was then drained from the resin and washed thoroughly with DMF several times. The protected amino acid Fmoc-Thr (tBu) -OH (2.5 ml, 5 eq) prepared as a 0.2 M stock solution in DMF was then added, followed by 0.45 M (4.5 eq) HBTU [2- ( 1H-benzo-triazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate] was added. This is followed by 0.5 ml NMP
2M (10 eq) DIPEA (diisopropylethylamine) in (N-methylpyrrollidinone) was added. The coupling process consists of 20 watts of microwave power, 7
It was carried out for 5 minutes using a maximum temperature of 5 ° C. and bubbling with comparable nitrogen.
最初のカップリングの工程の後、反応容器から液体を排出して廃棄し、カップリングの工程を繰り返した。次いでサイクル1と同様のサイクル2を開始した。全てのアミノ酸を同様にして導入し、シークエンス全体を通して二重カップリングの方法を用いた。サイクル1〜3、19〜20、25〜26および30〜39は、カップリングの工程のすぐ後にキャッピングの手順を含んでいた。キャッピングは、NMP中の0.015M HOBTを含む0.5M無水酢酸7 mlおよび2M DIPEA溶液2 mlの添加により、多段階マイクロ波プロトコルを用いて行った:50ワットの電力で30秒間(最大温度65℃)、続いて30秒間のマイクロ波電
力オフ、続いて第2ラウンドの30秒間のマイクロ波電力オン(50ワット)、次いで再び30秒間のマイクロ波電力無し。次いで樹脂から液体を排出し、DMFで完全に洗浄した
。次のアミノ酸(Advanced Chemtech,米国ケンタッキー州ルイスビル)を用いた:サイク
ル1: Fmoc-Thr(OtBu)-OH; サイクル2: Fmoc-Ile-OH; サイクル3: Fmoc-Asn(Trt)-OH; サ
イクル4: Fmoc-His(Trt)-OH; サイクル5: Fmoc-Lys(Boc)-OH; サイクル6: Fmoc-Trp(Boc)-OH; サイクル7: Fmoc-Asp(OtBu)-OH; サイクル8: Fmoc-Asn(Trt)-OH; サイクル9: Fmoc-Lys(Boc)-OH; サイクル10: Fmoc-Lys(Boc)-OH; サイクル11: Fmoc-Gly-OH; サイクル12: Fmoc-Lys(Boc)-OH; サイクル13: Fmoc-Gln(Trt)-OH; サイクル14: Fmoc-Ala-OH; サイク
ル15: Fmoc-Leu-OH; サイクル16: Fmoc-Leu-OH; サイクル17: Fmoc-Trp(Boc)-OH; サイクル18: Fmoc-Asn(Trt)-OH; サイクル19: Fmoc-Val-OH; サイクル20: Fmoc-Phe-OH; サイクル21: Fmoc-Asp(OtBu)-OH; サイクル22: Fmoc-Gln(Trt)-OH; サイクル23: Fmoc-Gln(Trt)-OH; サイクル24: Fmoc-His(Trt)-OH; サイクル25: Fmoc-Ile-OH; サイクル26: Fmoc-Lys(Boc)-OH; サイクル27: Fmoc-Asp(OtBu)-OH; サイクル28: Fmoc-Met-OH; サイクル29: Fmoc-Ala-OH; サイクル30: Fmoc-Ile-OH; サイクル31: Fmoc-Tyr(tBu)-Ser(psiMe,Me,Pro)-OH; サイクル32: Fmoc-Asp(OtBu)-OH; サイクル33: Fmoc-Ser(tBu)-OH; サイクル34: Fmoc-A6c-OH. サイクル35: Fmoc-Phe-OH; サイクル36: Fmoc-Gly-Thr(psiMe,Me,Pro)-OH; サイクル37: Fmoc-Glu(OtBu)-OH; サイクル38: Fmoc-Ala-OH;およびサイクル39: Fmoc-Tyr(tBu)-OH。Fmoc-His(Trt)-OHに関するカップリングのプロトコルは、標準的なプロトコル
を少し修正したバージョンであった。最初の2分間マイクロ波電力をオフにし、続いてマイクロ波電力オンで4分間(20ワット;最大温度50℃)行った。一度ペプチドのバックボーンが完成したら、標準的なピペリジン処理を用いてN末端のFmoc基を除去した。次いで樹脂をDMFで完全に洗浄し、次いで移動用の溶媒としてDMFを用いて50 mlコニカルチ
ューブに戻した。
After the first coupling step, the liquid was drained from the reaction vessel and discarded, and the coupling step was repeated. Then, cycle 2 similar to cycle 1 was started. All amino acids were introduced in the same way and the double coupling method was used throughout the sequence. Cycles 1-3, 19-20, 25-26, and 30-39 included a capping procedure immediately after the coupling step. Capping was performed using a multi-stage microwave protocol by the addition of 7 ml of 0.5M acetic anhydride containing 0.015M HOBT in NMP and 2 ml of 2M DIPEA solution: 30 seconds at 50 watts power (maximum temperature 65 ° C. ), Followed by 30 seconds of microwave power off, followed by a second round of 30 seconds of microwave power on (50 watts), then again for 30 seconds of no microwave power. The liquid was then drained from the resin and washed thoroughly with DMF. The following amino acids (Advanced Chemtech, Louisville, KY, USA) were used: Cycle 1: Fmoc-Thr (OtBu) -OH; Cycle 2: Fmoc-Ile-OH; Cycle 3: Fmoc-Asn (Trt) -OH; Cycle 4: Fmoc-His (Trt) -OH; Cycle 5: Fmoc-Lys (Boc) -OH; Cycle 6: Fmoc-Trp (Boc) -OH; Cycle 7: Fmoc-Asp (OtBu) -OH; Cycle 8: Fmoc-Asn (Trt) -OH; Cycle 9: Fmoc-Lys (Boc) -OH; Cycle 10: Fmoc-Lys (Boc) -OH; Cycle 11: Fmoc-Gly-OH; Cycle 12: Fmoc-Lys (Boc ) -OH; Cycle 13: Fmoc-Gln (Trt) -OH; Cycle 14: Fmoc-Ala-OH; Cycle 15: Fmoc-Leu-OH; Cycle 16: Fmoc-Leu-OH; Cycle 17: Fmoc-Trp ( Cycle 18: Fmoc-Asn (Trt) -OH; Cycle 19: Fmoc-Val-OH; Cycle 20: Fmoc-Phe-OH; Cycle 21: Fmoc-Asp (OtBu) -OH; Cycle 22: Fmoc-Gln (Trt) -OH; Cycle 23: Fmoc-Gln (Trt) -OH; Cycle 24: Fmoc-His (Trt) -OH; Cycle 25: Fmoc-Ile-OH; Cycle 26: Fmoc-Lys (Boc ) -OH; Cycle 27: Fmoc-Asp (OtBu) -OH; Cycle 28: Fmoc-Met-OH; Cycle 29: Fmoc-Ala-OH; Cycle 30: Fmoc-Ile-OH; Cycle 31: Fmoc-Tyr (tBu) -Ser (psiMe, Me, Pro) -OH; Cycle 32: Fmoc-Asp (OtBu) -OH Cycle 33: Fmoc-Ser (tBu) -OH; Cycle 34: Fmoc-A6c-OH. Cycle 35: Fmoc-Phe-OH; Cycle 36: Fmoc-Gly-Thr (psiMe, Me, Pro) -OH; Cycle 37: Fmoc-Glu (OtBu) -OH; cycle 38: Fmoc-Ala-OH; and cycle 39: Fmoc-Tyr (tBu) -OH. The coupling protocol for Fmoc-His (Trt) -OH was a slightly modified version of the standard protocol. The microwave power was turned off for the first 2 minutes, followed by microwave power on for 4 minutes (20 watts; maximum temperature 50 ° C.). Once the peptide backbone was completed, the N-terminal Fmoc group was removed using standard piperidine treatment. The resin was then washed thoroughly with DMF and then returned to the 50 ml conical tube using DMF as the transfer solvent.
5 mlの次の試薬で処理することによりその樹脂を脱保護し、樹脂から切り離した:5% TIS、2%水、5% (w/v)ジチオスレイトール(DTT)、88% TFA、および3.5時間混合させた。濾液を45 mlの冷無水エチルエーテルの中に集めた。沈殿物を冷却遠心機において3500 RPMで10分間遠心分離してペレットにした。エーテルをデカントし、ペプチドを新しいエ
ーテル中で再懸濁した。そのエーテルでの仕上げを合計2回行った。最後のエーテルでの洗浄の後、ペプチドを風乾させて残留したエーテルを除去した。ペプチドのペレットを8 mlのアセトニトリル(Acn)、続いて8 mlの脱イオン水中で再懸濁し、完全に溶解させた。
次いでそのペプチド溶液を質量分析により分析した。エレクトロスプレーイオン化を用いた質量分析は4970.7ダルトンの質量を含む主生成物を同定した;これはその直鎖状生成物と一致する。その粗生成物(おおよそ500 mg)を、250 x 4.6 mm C18カラム(Phenomenex;米国カリフォルニア州トーランス)を用いるHPLCにより、30分間にわたる2〜80%アセト
ニトリル(0.1% TFA)の勾配を用いて分析した。次いでその粗製のペプチドを、N-プロピルマレイミド(Pma)を用いて誘導体化し、システイン側鎖上のプロピルスクシンイミド(Psu)誘導体を生成した。その粗製の直鎖状ペプチドを、炭酸アンモニウムを用いてpH 6.5に調節した水の中で5 mg/mlで溶かした(brought up)。5当量のPmaを、30秒間一定して攪拌しながら添加した。過剰なPmaを5当量のジチオスレイトール(DTT)を用いて抑えた(quenched)。次いでその誘導体化したペプチドの溶液を質量分析により分析した。質量分析は、5109.7ダルトンの質量を含む主生成物を同定した;これは望まれるPsu誘導体化生成物と
一致する。次いでその生成物を分取HPLCにより前回と同様の勾配を用いて精製した。その精製された生成物を、純度に関してHPLCにより(96.60%)、および質量分析により(5108.9
ダルトン)分析し、続いて凍結乾燥した。凍結乾燥の後、10.3 mgの精製された生成物が得られ、これは2%の収率を表している。
The resin was deprotected and cleaved from the resin by treatment with 5 ml of the following reagents: 5% TIS, 2% water, 5% (w / v) dithiothreitol (DTT), 88% TFA, and Mix for 3.5 hours. The filtrate was collected in 45 ml of cold anhydrous ethyl ether. The precipitate was pelleted by centrifuging at 3500 RPM for 10 minutes in a refrigerated centrifuge. The ether was decanted and the peptide was resuspended in fresh ether. The ether finishing was performed a total of 2 times. After the last ether wash, the peptide was air dried to remove residual ether. The peptide pellet was resuspended in 8 ml acetonitrile (Acn) followed by 8 ml deionized water to completely dissolve.
The peptide solution was then analyzed by mass spectrometry. Mass spectrometry using electrospray ionization identified a major product containing a mass of 4970.7 daltons; this is consistent with its linear product. The crude product (approximately 500 mg) was analyzed by HPLC using a 250 x 4.6 mm C18 column (Phenomenex; Torrance, CA, USA) with a gradient of 2-80% acetonitrile (0.1% TFA) over 30 minutes. . The crude peptide was then derivatized with N-propylmaleimide (Pma) to produce a propylsuccinimide (Psu) derivative on the cysteine side chain. The crude linear peptide was brought up at 5 mg / ml in water adjusted to pH 6.5 with ammonium carbonate. 5 equivalents of Pma were added with constant stirring for 30 seconds. Excess Pma was quenched with 5 equivalents of dithiothreitol (DTT). The derivatized peptide solution was then analyzed by mass spectrometry. Mass spectrometry identified a major product containing a mass of 5109.7 Dalton; this is consistent with the desired Psu derivatized product. The product was then purified by preparative HPLC using the same gradient as before. The purified product was purified by HPLC (96.60%) for purity and by mass spectrometry (5108.9
Dalton) analysis followed by lyophilization. After lyophilization, 10.3 mg of purified product was obtained, representing a yield of 2%.
実施例18:[A6c 7 , Orn 35 (N-C(O)-(CH 2 ) 12 -CH 3 )]hGIP(1-42)-OH
Liberty Peptide Synthesizer (CEM;米国ノースキャロライナ州マシューズ)上で、0.1
mmoleスケールで、マイクロ波支援Fmoc化学を用いる固相ペプチド合成を用いてペプチド
を組み立てた。プレロードされたFmoc-Gln(Trt)-Wang樹脂(0.59 mmole/g;Novabiochem,米国カリフォルニア州サンディエゴ)を用いてC末端酸ペプチドを生成した。その樹脂(0.17 g)を50 mlコニカルチューブの中に、15 mlのジメチルホルムアミド(DMF)と共に置き、合成機上の樹脂の位置に入れた。次いでその樹脂を、自動化されたプロセスにより定量的に反応容器に移した。0.1 mmoleスケールでの合成のための標準的なLiberty合成プロトコルを用いた。このプロトコルには、DMF中の0.1M N-ヒドロキシベンゾトリアゾール(HOBT)を含む20% ピペリジン7 mlを用いた最初の処理によるN末端のFmoc部分の脱保護が含まれている。その最初の脱保護の工程は、マイクロ波電力(45ワット、最大温度75℃)および窒素による泡立て(3秒間オン/7秒間オフ)を用いて30秒間であった。次いで反応容器から液体を排出し、それが3分間の期間であること以外は第1の処理と同じである第2のピペリジン処理を行った。次いで樹脂から液体を排出し、DMFで数回、完全に洗浄
した。次いでDMF中で0.2Mのストック溶液として調製した保護されたアミノ酸Fmoc-Thr(tBu)-OH(2.5 ml, 5当量)、続いて1.0 mlのDMF中0.45M (4.5当量) HBTU [2-(1H-ベンゾ-トリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスフェート]を添加した。これに続き0.5 mlのNMP (N-メチルピロリジノン(N-methylpyrrollidinone))中2M
(10当量) DIPEA (ジイソプロピルエチルアミン)を添加した。カップリングの工程は、20ワットのマイクロ波電力、75℃の最大温度、および同程度の窒素による泡立てを用いて5分間行った。
Example 18: [A6c 7, Orn 35 (NC (O) - (CH 2) 12 -CH 3)] hGIP (1-42) -OH
0.1 on the Liberty Peptide Synthesizer (CEM; Matthews, North Carolina, USA)
Peptides were assembled using solid phase peptide synthesis using microwave assisted Fmoc chemistry on a mmole scale. C-terminal acid peptides were generated using preloaded Fmoc-Gln (Trt) -Wang resin (0.59 mmole / g; Novabiochem, San Diego, CA, USA). The resin (0.17 g) was placed in a 50 ml conical tube with 15 ml dimethylformamide (DMF) and placed in the resin position on the synthesizer. The resin was then quantitatively transferred to the reaction vessel by an automated process. A standard Liberty synthesis protocol for synthesis on the 0.1 mmole scale was used. This protocol includes deprotection of the N-terminal Fmoc moiety by initial treatment with 7 ml of 20% piperidine containing 0.1M N-hydroxybenzotriazole (HOBT) in DMF. The initial deprotection step was 30 seconds using microwave power (45 watts, maximum temperature 75 ° C.) and nitrogen bubbling (3 seconds on / 7 seconds off). The liquid was then drained from the reaction vessel and a second piperidine treatment was performed which was the same as the first treatment except that it was for a period of 3 minutes. The liquid was then drained from the resin and washed thoroughly with DMF several times. The protected amino acid Fmoc-Thr (tBu) -OH (2.5 ml, 5 eq) prepared as a 0.2 M stock solution in DMF was then added, followed by 0.45 M (4.5 eq) HBTU [2- ( 1H-benzo-triazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate] was added. This is followed by 2M in 0.5 ml NMP (N-methylpyrrolidinone).
(10 eq) DIPEA (diisopropylethylamine) was added. The coupling process was performed for 5 minutes using 20 watts of microwave power, a maximum temperature of 75 ° C., and comparable bubbling with nitrogen.
最初のカップリングの工程の後、反応容器から液体を排出して廃棄し、カップリングの工程を繰り返した。次いでサイクル1と同様のサイクル2を開始した。全てのアミノ酸を同様にして導入し、シークエンス全体を通して二重カップリングの方法を用いた。サイクル1〜3、19〜20、25〜26および30〜39は、カップリングの工程のすぐ後にキャッピングの手順を含んでいた。キャッピングは、NMP中の0.015M HOBTを含む0.5M無水酢酸7 mlおよび2M DIPEA溶液2 mlの添加により、多段階マイクロ波プロトコルを用いて行った:50ワットの電力で30秒間(最大温度65℃)、続いて30秒間のマイクロ波電力オフ、続いて第2ラウンドの30秒間のマイクロ波電力オン(50ワット)、次いで再び30秒間のマイクロ波電力無し。次いで樹脂から液体を排出し、DMFで完全に洗浄した
。次のアミノ酸(Advanced Chemtech,米国ケンタッキー州ルイスビル)を用いた:サイク
ル1: Fmoc-Thr(tBu)-OH; サイクル2: Fmoc-Ile-OH; サイクル3: Fmoc-Asn(Trt)-OH; サイクル4: Fmoc-His(Trt)-OH; サイクル5: Fmoc-Lys(Boc)-OH; サイクル6: Fmoc-Trp(Boc)-OH; サイクル7: Fmoc-Orn(Mtt)-OH; サイクル8: Fmoc-Asn(Trt)-OH; サイクル9: Fmoc-Lys(Boc)-OH; サイクル10: Fmoc-Lys(Boc)-OH; サイクル11: Fmoc-Gly-OH; サイクル12: Fmoc-Lys(Boc)-OH; サイクル13: Fmoc-Gln(Trt)-OH; サイクル14: Fmoc-Ala-OH; サイクル15: Fmoc-Leu-OH; サイクル16: Fmoc-Leu-OH; サイクル17: Fmoc-Trp(Boc)-OH; サイクル18: Fmoc-Asn(Trt)-OH; サイクル19: Fmoc-Val-OH; サイクル20: Fmoc-Phe-OH; サイクル21: Fmoc-Asp(OtBu)-OH; サイクル22: Fmoc-Gln(Trt)-OH; サイクル23: Fmoc-Gln(Trt)-OH;
サイクル24: Fmoc-His(Trt)-OH; サイクル25: Fmoc-Ile-OH; サイクル26: Fmoc-Lys(Boc)-OH; サイクル27: Fmoc-Asp(OtBu)-OH; サイクル28: Fmoc-Met-OH; サイクル29: Fmoc-Ala-OH; サイクル30: Fmoc-Ile-OH; サイクル31: Fmoc-Tyr(tBu)-Ser(psiMe,Me,Pro)-OH; サイクル32: Fmoc-Asp(OtBu)-OH; サイクル33: Fmoc-Ser(tBu)-OH; サイクル34: Fmoc-A6c-OH; サイクル35: Fmoc-Phe-OH; サイクル36: Fmoc-Gly-Thr(psiMe,Me,Pro)-OH; サイクル37: Fmoc-Glu(OtBu)-OH; サイクル38: Fmoc-Ala-OH;およびサイクル39: Boc-Tyr(tBu)-OH。Fmoc-His(Trt)-OHに関するカップリングのプロトコルは、標準的なプロトコルを少し修正したバージョンであった。最初の2分間マイクロ波電力をオフにし、続いてマイクロ波電力オンで4分間(20ワット;最大温度50℃)行った。一度ペプチドのバックボーンが完成したら、樹脂を12 mlのジクロロメタン(DCM)中1%トリフルオロ酢酸(TFA) / 5%トリイソプロピルシラン(TIS)で5分間、N2の散布の程度(sparge rate)を5秒間のオンおよび10秒間のオフで処理した。次いで樹脂から液体を排出し、再度DCM中1% TFA / 5% TISで5分間処理した。オルニチン側鎖からMtt部分を効果的に除去するため、これを合計
7回行った。その樹脂をDCMを用いて数回、完全に洗浄し、次いでオルニチンのδN上の
残留したTFA塩を中和するために標準的なピペリジン処理により処理した。DMF中0.2M溶液として調製したミリスチン酸(CH3-(CH2)12-COOH; AldRiCH,米国ミズーリ州セントルイス)を、標準的なアミノ酸のカップリングのプロトコルを用いてオルニチン側鎖にカップリ
ングさせた。次いで樹脂をDMFで完全に洗浄し、次いで移動用の溶媒としてDMFを用いて50
mlコニカルチューブに戻した。
After the first coupling step, the liquid was drained from the reaction vessel and discarded, and the coupling step was repeated. Then, cycle 2 similar to cycle 1 was started. All amino acids were introduced in the same way and the double coupling method was used throughout the sequence. Cycles 1-3, 19-20, 25-26, and 30-39 included a capping procedure immediately after the coupling step. Capping was performed using a multi-stage microwave protocol by the addition of 7 ml of 0.5M acetic anhydride containing 0.015M HOBT in NMP and 2 ml of 2M DIPEA solution: 30 seconds at 50 watts power (maximum temperature 65 ° C. ), Followed by 30 seconds of microwave power off, followed by a second round of 30 seconds of microwave power on (50 watts), then again for 30 seconds of no microwave power. The liquid was then drained from the resin and washed thoroughly with DMF. The following amino acids (Advanced Chemtech, Louisville, KY, USA) were used: Cycle 1: Fmoc-Thr (tBu) -OH; Cycle 2: Fmoc-Ile-OH; Cycle 3: Fmoc-Asn (Trt) -OH; Cycle 4: Fmoc-His (Trt) -OH; Cycle 5: Fmoc-Lys (Boc) -OH; Cycle 6: Fmoc-Trp (Boc) -OH; Cycle 7: Fmoc-Orn (Mtt) -OH; Cycle 8: Fmoc-Asn (Trt) -OH; Cycle 9: Fmoc-Lys (Boc) -OH; Cycle 10: Fmoc-Lys (Boc) -OH; Cycle 11: Fmoc-Gly-OH; Cycle 12: Fmoc-Lys (Boc ) -OH; Cycle 13: Fmoc-Gln (Trt) -OH; Cycle 14: Fmoc-Ala-OH; Cycle 15: Fmoc-Leu-OH; Cycle 16: Fmoc-Leu-OH; Cycle 17: Fmoc-Trp ( Cycle 18: Fmoc-Asn (Trt) -OH; Cycle 19: Fmoc-Val-OH; Cycle 20: Fmoc-Phe-OH; Cycle 21: Fmoc-Asp (OtBu) -OH; Cycle 22: Fmoc-Gln (Trt) -OH; Cycle 23: Fmoc-Gln (Trt) -OH;
Cycle 24: Fmoc-His (Trt) -OH; Cycle 25: Fmoc-Ile-OH; Cycle 26: Fmoc-Lys (Boc) -OH; Cycle 27: Fmoc-Asp (OtBu) -OH; Cycle 28: Fmoc- Cycle 29: Fmoc-Ala-OH; Cycle 30: Fmoc-Ile-OH; Cycle 31: Fmoc-Tyr (tBu) -Ser (psiMe, Me, Pro) -OH; Cycle 32: Fmoc-Asp ( OtBu) -OH; Cycle 33: Fmoc-Ser (tBu) -OH; Cycle 34: Fmoc-A6c-OH; Cycle 35: Fmoc-Phe-OH; Cycle 36: Fmoc-Gly-Thr (psiMe, Me, Pro) -OH; Cycle 37: Fmoc-Glu (OtBu) -OH; Cycle 38: Fmoc-Ala-OH; and Cycle 39: Boc-Tyr (tBu) -OH. The coupling protocol for Fmoc-His (Trt) -OH was a slightly modified version of the standard protocol. The microwave power was turned off for the first 2 minutes, followed by microwave power on for 4 minutes (20 watts; maximum temperature 50 ° C.). Once the peptide backbone is complete, the resin can be sprinkled with 1% trifluoroacetic acid (TFA) / 5% triisopropylsilane (TIS) in 12 ml of dichloromethane (DCM) for 5 minutes and the N 2 sparge rate. Treated with 5 seconds on and 10 seconds off. The liquid was then drained from the resin and again treated with 1% TFA / 5% TIS in DCM for 5 minutes. This was done a total of 7 times to effectively remove the Mtt moiety from the ornithine side chain. The resin was washed thoroughly several times with DCM and then treated with standard piperidine treatment to neutralize residual TFA salt on ornithine δN. Myristic acid (CH 3- (CH 2 ) 12 -COOH; AldRiCH, St. Louis, MO, USA) prepared as a 0.2M solution in DMF was coupled to the ornithine side chain using standard amino acid coupling protocols. It was. The resin is then thoroughly washed with DMF and then 50% using DMF as the transfer solvent.
Returned to ml conical tube.
5 mlの次の試薬で処理することによりその樹脂を脱保護し、樹脂から切り離した:5% TIS、2%水、5% (w/v)ジチオスレイトール(DTT)、88% TFA、および3.5時間混合させた。濾液を45 mlの冷無水エチルエーテルの中に集めた。沈殿物を冷却遠心機において3500 RPMで10分間遠心分離してペレットにした。エーテルをデカントし、ペプチドを新しいエ
ーテル中で再懸濁した。そのエーテルでの仕上げを合計2回行った。最後のエーテルでの洗浄の後、ペプチドを風乾させて残留したエーテルを除去した。ペプチドのペレットを8 mlのアセトニトリル(Acn)、続いて8 mlの脱イオン水中で再懸濁し、完全に溶解させた。
次いでそのペプチド溶液を質量分析により分析した。エレクトロスプレーイオン化を用いた質量分析は5205.1ダルトンの質量を含む主生成物を同定した;これは望まれる直鎖状生成物と一致する。その粗生成物(おおよそ500 mg)を、250 x 4.6 mm C18カラム(Phenomenex;米国カリフォルニア州トーランス)を用いるHPLCにより、30分間にわたる2〜80%アセ
トニトリル(0.1% TFA)の勾配を用いて分析した。分析的HPLCは、50%の純度を有する生成
物を同定した。次いでそのペプチドを、C18カラムを備えた分取HPLC上で、同様の溶離勾
配を用いて精製した。その精製された生成物を、純度に関してHPLCにより(97.40%)、および質量分析により(5204.6ダルトン)再分析し、続いて凍結乾燥させた。凍結乾燥の後、6.2 mgの精製された生成物が得られ、これは1.2%の収率を表している。
The resin was deprotected and cleaved from the resin by treatment with 5 ml of the following reagents: 5% TIS, 2% water, 5% (w / v) dithiothreitol (DTT), 88% TFA, and Mix for 3.5 hours. The filtrate was collected in 45 ml of cold anhydrous ethyl ether. The precipitate was pelleted by centrifuging at 3500 RPM for 10 minutes in a refrigerated centrifuge. The ether was decanted and the peptide was resuspended in fresh ether. The ether finishing was performed a total of 2 times. After the last ether wash, the peptide was air dried to remove residual ether. The peptide pellet was resuspended in 8 ml acetonitrile (Acn) followed by 8 ml deionized water to completely dissolve.
The peptide solution was then analyzed by mass spectrometry. Mass spectrometry using electrospray ionization identified a major product containing a mass of 5205.1 daltons; this is consistent with the desired linear product. The crude product (approximately 500 mg) was analyzed by HPLC using a 250 x 4.6 mm C18 column (Phenomenex; Torrance, CA, USA) with a gradient of 2-80% acetonitrile (0.1% TFA) over 30 minutes. . Analytical HPLC identified a product with 50% purity. The peptide was then purified on a preparative HPLC equipped with a C18 column using a similar elution gradient. The purified product was reanalyzed for purity by HPLC (97.40%) and by mass spectrometry (5204.6 Dalton) followed by lyophilization. After lyophilization, 6.2 mg of purified product was obtained, representing a yield of 1.2%.
本明細書で開示されたPEG化されたGIP化合物は、実質的に実施例15の化合物の合成に関して記述された手順に従って、出発物質として実施例15において用いられたN-プロピルマレイミドの代わりにPEG-マレイミドを用いることにより合成することができる。 The PEGylated GIP compound disclosed herein can be obtained by replacing PEG in place of N-propylmaleimide used in Example 15 as a starting material, substantially following the procedure described for the synthesis of the compound of Example 15. -It can be synthesized by using maleimide.
当業者は、本発明の他のペプチドを、前記の実施例において開示された合成手順に類似した合成手順を用いて調製することができる。本明細書において例示した化合物に関する物理的データを表1に示す。 One skilled in the art can prepare other peptides of the invention using synthetic procedures similar to the synthetic procedures disclosed in the previous examples. The physical data for the compounds exemplified herein is shown in Table 1.
表1Table 1
機能的アッセイ
A.インビトロhGIP受容体結合アッセイ
ヒトの組換えGIP受容体を発現しているCHO-K1クローン細胞を、氷冷した50mM トリ
ス-HCl中でBrinkman Polytron(設定6、15秒)を用いてホモジナイズし、次いで39,000 gでの10分間の遠心分離を2回、間で新しい緩衝液に再懸濁して行うことにより、イ
ンビトロ受容体結合アッセイのための膜を調製した。そのアッセイに関して、洗浄した膜調製物の部分量(aliquots)を、50mM トリス-HCl、0.1 mg/mlバシトラシン、および0.1% BSA中0.05nM [125I]GIP (おおよそ2200 Ci/mmol)と共に25℃で100分間保温した。最
終的なアッセイ体積は0.5 mlであった。Brandel濾過マニホールドを用いてGF/Cフィルタ
ー(0.5%ポリエチレンイミンに予め浸したもの)を通して急速に濾過することにより、保温を終了させた。次いでそれぞれのチューブおよびフィルターを、5 ml部分量の氷冷した
緩衝液で3回洗浄した。特異的な結合は、結合した全ての放射性リガンドから1000nMのGIPの存在下で結合した放射性リガンドを引いたものとして定義された。本明細書で例示した化合物に関するインビトロhGIP受容体結合のデータを表2に示す。
Functional Assay A. In Vitro hGIP Receptor Binding Assay CHO-K1 clonal cells expressing human recombinant GIP receptor are homogenized using Brinkman Polytron (setting 6, 15 seconds) in ice-cold 50 mM Tris-HCl, then Membranes for in vitro receptor binding assays were prepared by two 10 minute centrifugations at 39,000 g, resuspended in fresh buffer in between. For that assay, the aliquots of the washed membrane preparation were mixed at 25 ° C. with 50 mM Tris-HCl, 0.1 mg / ml bacitracin, and 0.05 nM [ 125 I] GIP (approximately 2200 Ci / mmol) in 0.1% BSA. For 100 minutes. The final assay volume was 0.5 ml. Incubation was terminated by rapid filtration through a GF / C filter (pre-soaked in 0.5% polyethyleneimine) using a Brandel filtration manifold. Each tube and filter was then washed 3 times with a 5 ml aliquot of ice-cold buffer. Specific binding was defined as all bound radioligand minus the bound radioligand in the presence of 1000 nM GIP. In vitro hGIP receptor binding data for the compounds exemplified herein is shown in Table 2.
B.ヒトおよびラットの血漿内半減期アッセイ
GIPペプチド(50 μL 1 mg/ml)を450μLの血漿(ヒトまたはラット)に添加し、短時間ボルテックスし(vertexed)、37℃で保温した。0、1、2、3、4、8、24、32、48、56、72時間の時点のような様々な時点において50 μLを分離し、マイクロ遠心チューブの中で5 μLのギ酸および150 μLのアセトニトリルと混合し、ボルテックスし(vertexed)、10K rpmで10分間遠心分離した。上清を注入バイアルに移し、LC-MSにより分析した。LC-MSシステムはESIプローブを有するAPI4000質量分析器で構成されていた。
正イオンモードおよび完全スキャン検出を用いた。HPLCでの分離を、Luna 3μ C8 (2), 2
x 30 mmカラム上で、90% Aから90% Bまでの勾配を用いて、0.3 ml/分の流速において1
0分間で実施した。緩衝液Aは水中1%ギ酸であり、緩衝液Bは1%ギ酸アセトニトリルであった。本明細書で例示した化合物に関するヒトおよびラットの血漿内半減期のデータを表2に示す。
B. Human and rat plasma half-life assay GIP peptide (50 μL 1 mg / ml) was added to 450 μL of plasma (human or rat), vortexed briefly and incubated at 37 ° C. Separate 50 μL at various time points, such as 0, 1, 2, 3, 4, 8, 24, 32, 48, 56, 72 hour time points, 5 μL formic acid and 150 μL in a microcentrifuge tube. Of acetonitrile, vortexed and centrifuged at 10K rpm for 10 minutes. The supernatant was transferred to an injection vial and analyzed by LC-MS. The LC-MS system consisted of an API4000 mass spectrometer with an ESI probe.
Positive ion mode and full scan detection were used. Separation by HPLC, Luna 3μ C8 (2), 2
1 x 30 mm column with a gradient from 90% A to 90% B at a flow rate of 0.3 ml / min.
Performed in 0 minutes. Buffer A was 1% formic acid in water and buffer B was 1% acetonitrile formate. The human and rat plasma half-life data for the compounds exemplified herein are shown in Table 2.
表2Table 2
C.環状AMP刺激の測定
1 x 105個のヒトの組換えGIP受容体を発現しているCHO-K1細胞またはRIN-5Fインス
リノーマ細胞を、24ウェル細胞培養プレート(Corning Incorporate,米国ニューヨーク州コーニング)の中に一夜まいた。そのアッセイに関して、細胞を0.55mM IBMX(Sigma,米国ミズーリ州セントルイス)を含むpH 7.3に調節したハンクス緩衝塩溶液(Sigma,米国ミ
ズーリ州セントルイス)500 μl中で10分間前保温した(preincubated)。次いでGIPまたはそのアナログを、100 nMの濃度で添加した。37℃で30分間の保温の後、プレートを氷上に置き、500 μlの氷冷無水エタノールを添加して反応を止めた。ウェルの内容物
を集め、4℃において2,700 gで20分間遠心分離して細胞破壊片を除去した。上清中のcAMPレベルを放射性免疫測定 (New England Nuclear,米国マサチューセッツ州ボストン)
により決定した。
C. Measurement of cyclic AMP stimulation
CHO-K1 cells or RIN-5F insulinoma cells expressing 1 × 10 5 human recombinant GIP receptors were plated overnight in 24-well cell culture plates (Corning Incorporate, Corning, NY, USA). For that assay, cells were preincubated for 10 minutes in 500 μl of Hanks buffered salt solution (Sigma, St. Louis, MO) adjusted to pH 7.3 containing 0.55 mM IBMX (Sigma, St. Louis, MO). GIP or its analog was then added at a concentration of 100 nM. After incubation at 37 ° C. for 30 minutes, the plate was placed on ice, and 500 μl of ice-cold absolute ethanol was added to stop the reaction. The contents of the wells were collected and centrifuged at 2,700 g for 20 minutes at 4 ° C. to remove cell debris. Radioimmunoassay of cAMP levels in supernatant (New England Nuclear, Boston, Massachusetts, USA)
Determined by.
D.正常なラットにおけるインビボでのインスリン分泌の測定
おおよそ275〜300 gの体重を有するオスのスプラーグドーリーラットを実験の対象として用いた。処理の前の日に、クロロハイドレートの下で頚静脈を通して右心房カニューレを挿入した。それぞれのカニューレを100 u/mlヘパリン生理食塩水で満たし、結んだ。化合物またはビヒクル(生理食塩水/0.25% BSA)を投与する前に、おおよそ18時間ラットを絶食させた。実験の日に、化合物の部分量を解かし、室温に戻し、完全にボルテックスした。溶液から生じる化合物のあらゆる兆候に関して注意深くチェックした。化合物/グル
コースの注入の10分前に、500 μlの血液試料を吸い出し、等体積のヘパリン添加生理
食塩水(10 u/ml)と入れ替えた。時間0において、カニューレを通して500 μlの血液試料を吸い出した。次に、ビヒクルまたは化合物の適切な用量のどちらかをカニューレの中に注入し、グルコース(1 g/kg)またはビヒクルの溶液で押し入れた。最後に、500 μlの体
積のヘパリン添加生理食塩水(10 u/ml)を用いて残ったグルコースをカニューレを通して
押し入れた。さらに500 μlの血液試料を、グルコースの投与の2.5、5、10、およ
び20分後に吸い出した;それぞれの直後に500 μlのヘパリン添加生理食塩水(10 u/ml)をカニューレを通して大量瞬時(bolus)静脈内注入した。血漿を血液試料から遠心分離に
より集め、インスリン含有量に関するアッセイまで−20℃で保管した。
D. Measurement of in vivo insulin secretion in normal rats Male Sprague Dawley rats having a body weight of approximately 275-300 g were used as the subjects of the experiment. The day before treatment, a right atrial cannula was inserted through the jugular vein under chlorohydrate. Each cannula was filled and tied with 100 u / ml heparin saline. Rats were fasted for approximately 18 hours before administration of compound or vehicle (saline / 0.25% BSA). On the day of the experiment, a portion of the compound was thawed, returned to room temperature and vortexed completely. Carefully checked for any signs of compound coming out of solution. Ten minutes prior to compound / glucose infusion, a 500 μl blood sample was aspirated and replaced with an equal volume of heparinized saline (10 u / ml). At time 0, a 500 μl blood sample was drawn through the cannula. Next, either the vehicle or the appropriate dose of compound was injected into the cannula and pushed in with glucose (1 g / kg) or vehicle solution. Finally, the remaining glucose was pushed through the cannula using a 500 μl volume of heparinized saline (10 u / ml). An additional 500 μl of blood sample was aspirated 2.5, 5, 10, and 20 minutes after administration of glucose; immediately after each, 500 μl of heparinized saline (10 u / ml) was flushed through the cannula. (bolus) was injected intravenously. Plasma was collected from blood samples by centrifugation and stored at −20 ° C. until assayed for insulin content.
図1は、実施例1〜7の化合物および天然のGIPのスプラーグドーリーラットのインスリン放出に対するインビボでの作用を示す。図1で示した総インスリン分泌の数値を表3において要約する。 FIG. 1 shows the in vivo effect of the compounds of Examples 1-7 and natural GIP on insulin release in Sprague-Dawley rats. The total insulin secretion values shown in FIG. 1 are summarized in Table 3.
表3Table 3
実施例20の化合物のインビボでの作用は、別の試験において上記と同じ実験条件の下で測定し、実施例20の化合物に関する総インスリン分泌の数値を表4において要約する。 The in vivo effect of the compound of Example 20 was measured in a separate test under the same experimental conditions as described above, and the total insulin secretion values for the compound of Example 20 are summarized in Table 4.
表4Table 4
投与
この発明のペプチドは、医薬的に許容できる塩類の形で提供することができる。その塩類の例には、有機酸(例えば酢酸、乳酸、マレイン酸、クエン酸、リンゴ酸、アスコルビン酸、コハク酸、安息香酸、メタンスルホン酸、トルエンスルホン酸、またはパモ酸(pamoic acid))、無機酸(例えば塩酸、硫酸、またはリン酸)およびポリマー性の酸(例え
ばタンニン酸、カルボキシメチルセルロース、ポリ乳酸、ポリグリコール酸、またはポリ乳酸−ポリグリコール酸のコポリマー類)により形成される塩類が含まれるが、それらに限定されない。本発明のペプチドの塩を作る典型的な方法は当技術では周知であり、標準的な塩交換の方法により成し遂げることができる。従って、本発明のペプチドのTFA塩(TFA塩は分取HPLCを用いてTFAを含む緩衝溶液で溶離することによるペプチドの精製の結果
得られる)は別の塩に、例えばそのペプチドを少量の0.25 N酢酸水溶液中で溶解することにより酢酸塩に変換することができる。得られた溶液をセミ分取(semi-prep)HPLCカラム(Zorbax, 300 SB, C-8)に適用する。そのカラムを(1)0.1N酢酸アンモニウム水溶液で0.5時間、(2)0.25N酢酸水溶液で0.5時間、および(3)4 ml/分の流速における直線勾配(30分間にわたる20%〜100%の溶液B)(溶液Aは0.25 N酢酸水溶液であり;溶液B
はアセトニトリル/水80:20中0.25 N酢酸である)を用いて溶離する。ペプチドを含む画
分を集め、凍結乾燥させる。
Administration The peptides of this invention can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include organic acids (eg acetic acid, lactic acid, maleic acid, citric acid, malic acid, ascorbic acid, succinic acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid, or pamoic acid), Includes salts formed with inorganic acids (eg, hydrochloric acid, sulfuric acid, or phosphoric acid) and polymeric acids (eg, tannic acid, carboxymethylcellulose, polylactic acid, polyglycolic acid, or polylactic acid-polyglycolic acid copolymers) However, it is not limited to them. Typical methods for making salts of the peptides of the present invention are well known in the art and can be accomplished by standard salt exchange methods. Thus, a TFA salt of a peptide of the present invention (a TFA salt obtained as a result of purification of the peptide using preparative HPLC and eluting with a buffer solution containing TFA) is converted to another salt, eg, a small amount of 0.25. It can be converted to an acetate salt by dissolving in N acetic acid aqueous solution. The resulting solution is applied to a semi-prep HPLC column (Zorbax, 300 SB, C-8). The column was (1) 0.5N aqueous 0.1N ammonium acetate solution, (2) 0.5N aqueous acetic acid solution 0.5 hour, and (3) a linear gradient at a flow rate of 4 ml / min (from 20% to 30 min. 100% solution B) (solution A is a 0.25 N aqueous acetic acid solution; solution B
Is 0.25 N acetic acid in acetonitrile / water 80:20). Fractions containing the peptide are collected and lyophilized.
この発明の組成物中の有効成分の用量は異なっていてよい;しかし、有効成分の量は適切な剤形が得られるようなものである必要がある。選択される用量は、望まれる療法的作用に、投与経路に、および治療の期間に依存する。一般に、この発明の活性に関する有効な用量は1 x 10-7〜200 mg/kg/日、好ましくは1 x 10-4〜100 mg/kg/日の範囲であり、それは1回量として、または多数回の用量に分けて投与することができる。 The dose of active ingredient in the compositions of this invention may vary; however, the amount of active ingredient should be such that a suitable dosage form is obtained. The dose selected will depend on the desired therapeutic effect, on the route of administration and on the duration of treatment. In general, an effective dose for the activity of this invention is in the range of 1 × 10 −7 to 200 mg / kg / day, preferably 1 × 10 −4 to 100 mg / kg / day, as a single dose, or It can be administered in multiple doses.
この発明の化合物は、経口、非経口(例えば筋内、腹膜内、静脈内または皮下の注射、または埋め込み)、経鼻、膣内、直腸内、舌下、または局所的投与経路により投与することができ、それぞれの投与経路に適した剤形を提供するために医薬的に許容できるキャリヤーと共に配合することができる。 The compounds of this invention may be administered orally, parenterally (eg, intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implantation), nasally, vaginally, rectally, sublingually, or by topical route of administration. And can be formulated with a pharmaceutically acceptable carrier to provide a dosage form suitable for each route of administration.
経口投与のための固体剤形には、カプセル、錠剤、丸剤、粉末および顆粒が含まれる。その固体剤形において、有効化合物は少なくとも1種類の不活性な医薬的に許容できるキャリヤー、例えばスクロース、ラクトースまたはデンプンと混合される。その剤形はその不活性な希釈剤以外の追加の物質、例えば潤滑剤、例えばステアリン酸マグネシウムも含むことができ、それが通常の慣習である。カプセル、錠剤および丸剤の場合、その剤形は緩衝剤も含んでいてよい。錠剤および丸剤はさらに腸溶コーティングを用いて調製することができる。 Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In that solid dosage form, the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. The dosage form may also contain additional materials other than the inert diluent, such as a lubricant, such as magnesium stearate, which is a common practice. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
経口投与のための液体剤形には、当技術で一般的に用いられる不活性な希釈剤、例えば水を含む、医薬的に許容できる乳濁液、溶液、懸濁液、シロップ、エリキシルおよび同様のものが含まれるが、それらに限定されない。その不活性な希釈剤の他に、組成物は補助剤、例えば湿潤剤、乳濁化および懸濁化剤、ならびに甘味料、香味料および香料も含むことができる。 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, including inert diluents commonly used in the art, such as water. Are included, but are not limited thereto. Besides the inert diluent, the composition can also contain adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
非経口投与のためのこの発明に従う製剤には、無菌の水溶液または非水溶液、懸濁液、乳濁液および同様のものが含まれるが、それらに限定されない。非水性溶媒またはビヒクルの例には、プロピレングリコール、ポリエチレングリコール、植物油、例えばオリーブ油およびトウモロコシ油、ゼラチン、ならびに注射可能な有機エステル類、例えばオレイン酸エチルが含まれる。その剤形は補助剤、例えば保存、湿潤、乳濁化および分散剤も含んでいてよい。それらは例えば細菌を保持するフィルターを通す濾過により、組成物中に滅菌剤を組み込むことにより、組成物を照射することにより、または組成物を加熱することにより滅菌されてよい。それらは、滅菌水または何らかの他の無菌の注射可能な媒体に使用の直前に溶解することができる無菌の固体組成物の形で製造することもできる。 Formulations according to this invention for parenteral administration include, but are not limited to, sterile aqueous or non-aqueous solutions, suspensions, emulsions and the like. Examples of non-aqueous solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. The dosage forms may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized, for example, by filtration through a filter that retains bacteria, by incorporating a sterilant in the composition, by irradiating the composition, or by heating the composition. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
直腸内または膣内投与のための組成物は好ましくは坐剤であり、それは有効物質に加えて賦形剤、例えばカカオ脂(coca butter)または坐剤ワックスを含んでいてよい。 Compositions for rectal or vaginal administration are preferably suppositories, which may contain, in addition to the active substance, excipients such as cocoa butter or suppository wax.
経鼻または舌下投与のための組成物も、当技術で周知の標準的な賦形剤を用いて調製される。 Compositions for nasal or sublingual administration are also prepared using standard excipients well known in the art.
さらに、この発明の化合物は徐放性組成物、例えば下記の特許および特許出願において記述されている徐放性組成物で投与することができる。米国特許第5,672,659号は、生理活性薬剤およびポリエステルを含む徐放性組成物を教示する。米国特許第5,595,760号は、生理活性薬剤をゲル化可能な(gelable)形で含む徐放性組成物を教示
する。米国特許第5,821,221号は、生理活性薬剤およびキトサンを含むポリマー性徐放性組成物を教示する。米国特許第5,916,883号は、生理活性薬剤およびシクロデキストリンを含む徐放性組成物を教示する。PCT公開WO99/38536は、生理活性薬剤の吸収性徐放性組成物を教示する。PCT公開WO00/04916は、療法薬、例えばペプチドを含む微粒子を水中油プロセスで作るためのプロセスを教示する。PCT公開WO00/09166は、療法薬、例えばペプチドおよびリン酸化ポリマーを含む複合体を教示する。PCT公開WO00/25826は、療法薬、例えばペプチドおよび重合可能ではないラクトンを含むポリマーを含む複合体を教示する。
Furthermore, the compounds of this invention can be administered in sustained release compositions, such as the sustained release compositions described in the following patents and patent applications. US Pat. No. 5,672,659 teaches a sustained release composition comprising a bioactive agent and a polyester. U.S. Pat. No. 5,595,760 teaches a sustained release composition comprising a bioactive agent in a gelable form. US Pat. No. 5,821,221 teaches a polymeric sustained release composition comprising a bioactive agent and chitosan. US Pat. No. 5,916,883 teaches a sustained release composition comprising a bioactive agent and a cyclodextrin. PCT Publication WO 99/38536 teaches absorbable sustained release compositions of bioactive agents. PCT Publication WO 00/04916 teaches a process for making microparticles containing therapeutic agents, such as peptides, in an oil-in-water process. PCT Publication WO 00/09166 teaches a complex comprising a therapeutic agent, such as a peptide and a phosphorylated polymer. PCT Publication WO 00/25826 teaches a complex comprising a therapeutic agent, such as a peptide comprising a peptide and a non-polymerizable lactone.
別途定義しない限り、本明細書で用いられる全ての技術的および科学的な用語はこの発明が属する技術の当業者に一般的に理解されているものと同じ意味を有する。また、本明細書で言及された全ての刊行物、特許出願、特許および他の参考文献をそれぞれそのまま本明細書に援用する。 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, all publications, patent applications, patents, and other references mentioned in this specification are incorporated herein by reference in their entirety.
Claims (15)
(R2R3)-Tyr-Ala-Glu-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38- A39-A40-A41-A42-A43-R1、
(I)
ここで:
A4はGlyであり;
A5はThrであり;
A6はPheであり;
A7はIleまたはA6cであり;
A8はSerであり;
A9はAspであり;
A10はTyrであり;
A11はA5c、またはA6cであり;
A12はIleであり;
A13はAlaまたはAibであり;
A14はMet、A5c、A6c、またはNleであり;
A15はAspであり;
A16はLysであり;
A17はIleであり;
A18はHisであり;
A19はGlnであり;
A20はGlnであり;
A21はAspであり;
A22はPheであり;
A23はValであり;
A24はAsnであり;
A25はTrpであり;
A26はLeuであり;
A27はLeuであり;
A28はAlaであり;
A29はGlnであり;
A30はLysであり;
A31はGly、His、Orn(N-C(O)-(CH2)12-CH3)であり、または欠失しており;
A32はLys、Cys、Cys(スクシンイミド-N-(CH2)11-CH3)、Cys(スクシンイミド-N-(CH2)15-CH3)、Orn(N-C(O)-(CH2)10-CH3)、Orn(N-C(O)-(CH2)14-CH3)であり、または欠失しており;
A33はLys、Cys、Cys(スクシンイミド-N-(CH2)11-CH3)、Cys(スクシンイミド-N-(CH2)15-CH3)、Orn(N-C(O)-(CH2)10-CH3)、またはOrn(N-C(O)-(CH2)14-CH3)であり、または欠失しており;
A34はAsnであり、または欠失しており;
A35はAsp、Orn(N-C(O)-(CH2)12-CH3)であり、または欠失しており;
A36はTrpであり、または欠失しており;
A37はLysであり、または欠失しており;
A38はHisであり、または欠失しており;
A39はAsnであり、または欠失しており;
A40はIle、A5c、A6cであり、または欠失しており;
A41はThr、A5c、A6cであり、または欠失しており;
A42はGln、Cys(Psu)であり、または欠失しており;
A43はAdo、Ala、Asn、Asp、Cys、Cys(スクシンイミド-N-(CH2)11-CH3)、Cys(スクシンイミド-N-(CH2)15-CH3)、His、Lys(N-C(O)-(CH2)10-CH3)、Lys(N-C(O)-(CH2)14-CH3)、Orn(N-C(O)-(CH2)14-CH3)、Phe、Thr、Trpであり、または欠失しており;および
R1はOH、NH2、(C1-C30)アルコキシ、またはNH-X2-CH2-Z0であり、ここでX2は(C0-C30)炭化水素部分であり、Z0はH、OH、CO2H、またはCONH2であり;
R2およびR3のそれぞれは、H、(C1-C30)アルキル、(C1-C30)ヘテロアルキル、(C1-C30)アシル、(C2-C30)アルケニル、(C2-C30)アルキニル、アリール(C1-C30)アルキル、アリール(C1-C30)アシル、置換された(C1-C30)アルキル、置換された(C1-C30)ヘテロアルキル、置換された(C1-C30)アシル、置換された(C2-C30)アルケニル、置換された(C2-C30)アルキニル、置換されたアリール(C1-C30)アルキル、および置換されたアリール(C1-C30)アシルからなるグループから独立して選択され;但し、R2が(C1-C30)アシル、アリール(C1-C30)アシル、置換された(C1-C30)アシル、または置換されたアリール(C1-C30)アシルである場合、R3はH、(C1-C30)アルキル、(C1-C30)ヘテロアルキル、(C2-C30)アルケニル、(C2-C30)アルキニル、アリール(C1-C30)アルキル、置換された(C1-C30)アルキル、置換された(C1-C30)ヘテロアルキル、置換された(C2-C30)アルケニル、置換された(C2-C30)アルキニル、または置換されたアリール(C1-C30)アルキルであり;
ただし、A7、A11、A13、A14、A31、A33、A35、A40、A41、A42およびA43の少なくとも2つは、天然のhGIPの対応する位置のアミノ酸残基では無く、さらに共有結合的に連結されたPEG部分を含んでいてもよい。 A compound of formula (I), or a pharmaceutically acceptable salt thereof
(R 2 R 3 ) -Tyr-Ala-Glu-A 4 -A 5 -A 6 -A 7 -A 8 -A 9 -A 10 -A 11 -A 12 -A 13 -A 14 -A 15 -A 16 -A 17 -A 18 -A 19 -A 20 -A 21 -A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 32- A 33 -A 34 -A 35 -A 36 -A 37 -A 38 -A 39 -A 40 -A 41 -A 42 -A 43 -R 1 ,
(I)
here:
A 4 is Gly;
A 5 is Thr;
A 6 is Phe;
A 7 is Ile or A6c;
A 8 is Ser;
A 9 is Asp;
A 10 is Tyr;
A 11 is A5c, or A6c;
A 12 is Ile ;
A 13 is Ala or Aib;
A 14 is Met, A5c, A6c, or Nle;
A 15 is Asp;
A 16 is Lys;
A 17 is Ile;
A 18 is His;
A 19 is Gln;
A 20 is Gln;
A 21 is Asp;
A 22 is Phe;
A 23 is Val;
A 24 is Asn;
A 25 is Trp;
A 26 is Leu;
A 27 is Leu;
A 28 is Ala;
A 29 is Gln;
A 30 is Lys;
A 31 is Gly, His, Orn (NC (O)-(CH 2 ) 12 -CH 3 ) , or is deleted ;
A 32 is Lys, Cys, Cys (succinimide-N- (CH 2 ) 11 -CH 3 ), Cys (succinimide-N- (CH 2 ) 15 -CH 3 ), Orn (NC (O)-(CH 2 ) 10 -CH 3 ), Orn (NC (O)-(CH 2 ) 14 -CH 3 ), or deleted;
A 33 is Lys, Cys, Cys (succinimide-N- (CH 2 ) 11 -CH 3 ), Cys (succinimide-N- (CH 2 ) 15 -CH 3 ), Orn (NC (O)-(CH 2 ) 10 -CH 3), or Orn (NC (O) - ( CH 2) 14 is -CH 3), or is deleted with;
A 34 is Asn or is deleted;
A 35 is Asp, Orn (NC (O)-(CH 2 ) 12 -CH 3 ), or is deleted;
A 36 is Trp or is deleted;
A 37 is Lys or is deleted;
A 38 is His or deleted;
A 39 is Asn or is deleted;
A 40 is Ile, A5c, A6c, or is deleted;
A 41 is Thr, A5c, A6c, or is deleted;
A 42 is Gln, Cys (Psu), or is deleted;
A 43 is Ado, Ala, Asn, Asp, Cys, Cys (succinimide-N- (CH 2 ) 11 -CH 3 ), Cys (succinimide-N- (CH 2 ) 15 -CH 3 ), His, Lys (NC (O)-(CH 2 ) 10 -CH 3 ), Lys (NC (O)-(CH 2 ) 14 -CH 3 ), Orn (NC (O)-(CH 2 ) 14 -CH 3 ), Phe, Thr, Trp, or deleted; and
R 1 is OH, NH 2 , (C 1 -C 30 ) alkoxy, or NH-X 2 -CH 2 -Z 0 where X 2 is a (C 0 -C 30 ) hydrocarbon moiety and Z 0 is H, OH, CO 2 H, or CONH 2 ;
Each of R 2 and R 3 is H, (C 1 -C 30 ) alkyl, (C 1 -C 30 ) heteroalkyl, (C 1 -C 30 ) acyl, (C 2 -C 30 ) alkenyl, (C 2 -C 30 ) alkynyl, aryl (C 1 -C 30 ) alkyl, aryl (C 1 -C 30 ) acyl, substituted (C 1 -C 30 ) alkyl, substituted (C 1 -C 30 ) hetero Alkyl, substituted (C 1 -C 30 ) acyl, substituted (C 2 -C 30 ) alkenyl, substituted (C 2 -C 30 ) alkynyl, substituted aryl (C 1 -C 30 ) alkyl And independently selected from the group consisting of substituted aryl (C 1 -C 30 ) acyl; provided that R 2 is (C 1 -C 30 ) acyl, aryl (C 1 -C 30 ) acyl, substituted (C 1 -C 30 ) acyl, or substituted aryl (C 1 -C 30 ) acyl, R 3 is H, (C 1 -C 30 ) alkyl, (C 1 -C 30 ) heteroalkyl , (C 2 -C 30) alkenyl, (C 2 -C 30) alkynyl, aryl (C 1 -C 30) Alkyl, substituted (C 1 -C 30) alkyl, substituted (C 1 -C 30) heteroalkyl, substituted (C 2 -C 30) alkenyl, substituted (C 2 -C 30) alkynyl Or substituted aryl (C 1 -C 30 ) alkyl;
However, at least two of A 7 , A 11 , A 13 , A 14 , A 31 , A 33 , A 35 , A 40 , A 41 , A 42 and A 43 are amino acid residues at the corresponding positions of natural hGIP. It may also contain a PEG moiety that is covalently linked rather than a group.
ここで:
A4はGlyであり;
A5はThrであり;
A6はPheであり;
A7はIleであり;
A8はSerであり;
A9はAspであり;
A10はTyrであり;
A11はA5c、またはA6cであり;
A12はIleであり;
A13はAlaまたはAibであり;
A14はMet、A5c、またはNleであり;
A15はAspであり;
A16はLysであり;
A17はIleであり;
A18はHisであり;
A19はGlnであり;
A20はGlnであり;
A21はAspであり;
A22はPheであり;
A23はValであり;
A24はAsnであり;
A25はTrpであり;
A26はLeuであり;
A27はLeuであり;
A28はAlaであり;
A29はGlnであり;
A30はLysであり;
A31はGlyであり;
A32はLysであり;
A33はLysであり;
A34はAsnであり;
A35はAspであり;
A36はTrpであり;
A37はLysであり;
A38はHisであり;
A39はAsnであり;
A40はIle、またはA5cであり;
A41はThr、またはA5cであり;
A42はGlnであり;
A43はAsn、Asp、Hisであり、または欠失している。 The compound of claim 1, or a pharmaceutically acceptable salt thereof:
here:
A 4 is Gly;
A 5 is Thr;
A 6 is Phe;
A 7 is Ile;
A 8 is Ser;
A 9 is Asp;
A 10 is Tyr;
A 11 is A5c, or A6c;
A 12 is Ile;
A 13 is Ala or Aib;
A 14 is Met, A5c, or Nle;
A 15 is Asp;
A 16 is Lys;
A 17 is Ile;
A 18 is His;
A 19 is Gln;
A 20 is Gln;
A 21 is Asp;
A 22 is Phe;
A 23 is Val;
A 24 is Asn;
A 25 is Trp;
A 26 is Leu;
A 27 is Leu;
A 28 is Ala;
A 29 is Gln;
A 30 is Lys;
A 31 is Gly;
A 32 is Lys;
A 33 is Lys;
A 34 is Asn;
A 35 is Asp;
A 36 is Trp;
A 37 is Lys;
A 38 is His;
A 39 is Asn;
A 40 is Ile, or A5c;
A 41 is Thr, or A5c;
A 42 is Gln;
A 43 is Asn, Asp, His, or is missing.
(A5c11, 40)hGIP(1-42)-OH (SEQ ID NO:5);
(A5c11, His43)hGIP(1-43)-OH (SEQ ID NO:6);
(A5c11, Asn43)hGIP(1-43)-OH (SEQ ID NO:7);
(A5c11, Ala43)hGIP(1-43)-OH (SEQ ID NO:11);
(A5c11, Thr43)hGIP(1-43)-OH (SEQ ID NO:13);
(A6c11, 14, 41)hGIP(1-42)-OH (SEQ ID NO:14);
(A5c11, Ado43)hGIP(1-43)-OH (SEQ ID NO:16);
(A5c11, 14, His43)hGIP(1-43)-OH (SEQ ID NO:23);
(A5c11, Nle14, His43)hGIP(1-43)-OH (SEQ ID NO:24);
[A5c11, Orn32(N-C(O)-(CH2)14-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:25);
[A5c11, Orn33(N-C(O)-(CH2)14-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:26);
[A5c11, Orn43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH (SEQ ID NO:27);
[A5c11, Cys32(スクシンイミド-N-(CH2)15-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:28);
[A5c11, Cys33(スクシンイミド-N-(CH2)15-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:29);
[A5c11, Cys43(スクシンイミド-N-(CH2)15-CH3)]hGIP(1-43)-OH (SEQ ID NO:30);
(A5c11, His31)hGIP(1-31)-NH2 (SEQ ID NO:32);
(A5c11, 14)hGIP(1-30)-NH2 (SEQ ID NO:33);
(A5c11, 41, Cys32)hGIP(1-42)-NH2 (SEQ ID NO:34);
(A5c11, 41, Cys33)hGIP(1-42)-NH2 (SEQ ID NO:35);
(A5c11, 41, Cys43)hGIP(1-43)-NH2 (SEQ ID NO:36);
[A5c11, Orn32(N-C(O)-(CH2)10-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:37);
[A5c11, Orn33(N-C(O)-(CH2)10-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:38);
[A5c11, Lys43(N-C(O)-(CH2)10-CH3)]hGIP(1-43)-OH (SEQ ID NO:39);
[A5c11, Cys32(スクシンイミド-N-(CH2)11-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:40);
[A5c11, Cys33(スクシンイミド-N-(CH2)11-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:41);
[A5c11, Cys43(スクシンイミド-N-(CH2)11-CH3)]hGIP(1-43)-OH (SEQ ID NO:42);
[A5c11, Lys43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH (SEQ ID NO:43);
[A5c11, Orn32(N-C(O)-(CH2)14-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:44);もしくは
[A5c11, Orn33(N-C(O)-(CH2)14-CH3), His43]hGIP(1-43)-OH (SEQ ID NO:45);
である、請求項1に記載の化合物、またはその医薬的に許容できる塩。 (A5c 11, 41 ) hGIP (1-42) -OH (SEQ ID NO: 4);
(A5c 11, 40 ) hGIP (1-42) -OH (SEQ ID NO: 5);
(A5c 11 , His 43 ) hGIP (1-43) -OH (SEQ ID NO: 6);
(A5c 11 , Asn 43 ) hGIP (1-43) -OH (SEQ ID NO: 7);
(A5c 11 , Ala 43 ) hGIP (1-43) -OH (SEQ ID NO: 11);
(A5c 11 , Thr 43 ) hGIP (1-43) -OH (SEQ ID NO: 13);
(A6c 11, 14, 41 ) hGIP (1-42) -OH (SEQ ID NO: 14);
(A5c 11 , Ado 43 ) hGIP (1-43) -OH (SEQ ID NO: 16);
(A5c 11, 14 , His 43 ) hGIP (1-43) -OH (SEQ ID NO: 23);
(A5c 11 , Nle 14 , His 43 ) hGIP (1-43) -OH (SEQ ID NO: 24);
[A5c 11 , Orn 32 (NC (O)-(CH 2 ) 14 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 25);
[A5c 11 , Orn 33 (NC (O)-(CH 2 ) 14 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 26);
[A5c 11 , Orn 43 (NC (O)-(CH 2 ) 14 -CH 3 )] hGIP (1-43) -OH (SEQ ID NO: 27);
[A5c 11 , Cys 32 (succinimide-N- (CH 2 ) 15 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 28);
[A5c 11 , Cys 33 (succinimide-N- (CH 2 ) 15 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 29);
[A5c 11 , Cys 43 (succinimide-N- (CH 2 ) 15 -CH 3 )] hGIP (1-43) -OH (SEQ ID NO: 30);
(A5c 11 , His 31 ) hGIP (1-31) -NH 2 (SEQ ID NO: 32);
(A5c 11, 14 ) hGIP (1-30) -NH 2 (SEQ ID NO: 33);
(A5c 11, 41 , Cys 32 ) hGIP (1-42) -NH 2 (SEQ ID NO: 34);
(A5c 11, 41 , Cys 33 ) hGIP (1-42) -NH 2 (SEQ ID NO: 35);
(A5c 11, 41 , Cys 43 ) hGIP (1-43) -NH 2 (SEQ ID NO: 36);
[A5c 11 , Orn 32 (NC (O)-(CH 2 ) 10 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 37);
[A5c 11 , Orn 33 (NC (O)-(CH 2 ) 10 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 38);
[A5c 11 , Lys 43 (NC (O)-(CH 2 ) 10 -CH 3 )] hGIP (1-43) -OH (SEQ ID NO: 39);
[A5c 11 , Cys 32 (succinimide-N- (CH 2 ) 11 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 40);
[A5c 11 , Cys 33 (succinimide-N- (CH 2 ) 11 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 41);
[A5c 11 , Cys 43 (succinimide-N- (CH 2 ) 11 -CH 3 )] hGIP (1-43) -OH (SEQ ID NO: 42);
[A5c 11 , Lys 43 (NC (O)-(CH 2 ) 14 -CH 3 )] hGIP (1-43) -OH (SEQ ID NO: 43);
[A5c 11 , Orn 32 (NC (O)-(CH 2 ) 14 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 44); or
[A5c 11 , Orn 33 (NC (O)-(CH 2 ) 14 -CH 3 ), His 43 ] hGIP (1-43) -OH (SEQ ID NO: 45);
The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
(A5c11, 40)hGIP(1-42)-OH (SEQ ID NO:5);
(A5c11, His43)hGIP(1-43)-OH (SEQ ID NO:6);
(A5c11, Asn43)hGIP(1-43)-OH (SEQ ID NO:7); もしくは
(A5c11, 14, His43)hGIP(1-43)-OH (SEQ ID NO:23)
またはその医薬的に許容できる塩である、請求項2に記載の化合物。 (A5c 11, 41 ) hGIP (1-42) -OH (SEQ ID NO: 4);
(A5c 11, 40 ) hGIP (1-42) -OH (SEQ ID NO: 5);
(A5c 11 , His 43 ) hGIP (1-43) -OH (SEQ ID NO: 6);
(A5c 11 , Asn 43 ) hGIP (1-43) -OH (SEQ ID NO: 7); or
(A5c 11, 14 , His 43 ) hGIP (1-43) -OH (SEQ ID NO: 23)
Or a pharmaceutically acceptable salt thereof.
(A5c11, 41, Cys43)hGIP(1-43)-NH2 (SEQ ID NO:36);もしくは
[A5c11, Lys43(N-C(O)-(CH2)14-CH3)]hGIP(1-43)-OH (SEQ ID NO:43);
またはその医薬的に許容できる塩である、請求項3に記載の化合物。 (A5c 11 , His 43 ) hGIP (1-43) -OH (SEQ ID NO: 6);
(A5c 11, 41 , Cys 43 ) hGIP (1-43) -NH 2 (SEQ ID NO: 36); or
[A5c 11 , Lys 43 (NC (O)-(CH 2 ) 14 -CH 3 )] hGIP (1-43) -OH (SEQ ID NO: 43);
4. The compound of claim 3, which is or a pharmaceutically acceptable salt thereof.
またはその医薬的に許容できる塩である、請求項4に記載の化合物。 (A5c 11 , His 43 ) hGIP (1-43) -OH (SEQ ID NO: 6);
Or a pharmaceutically acceptable salt thereof.
A13はAlaまたはAibであり;
A14はMet、A5c、A6c、またはNleであり;
A31はGlyであり、または欠失しており;
A35はAspであり、または欠失しており;および
A42はGlnであり、または欠失している
請求項1に記載の化合物、またはその医薬的に許容できる塩。 A 7 is Ile;
A 13 is Ala or Aib;
A 14 is Met, A5c, A6c, or Nle;
A 31 is Gly or missing;
A 35 is Asp or is missing; and
The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A 42 is Gln or is deleted.
[A5c11, 41, Cys33(スクシンイミド-N-20K PEG)]hGIP(1-42)-NH2(SEQ ID NO:47);
[A5c11, 41, Cys43(スクシンイミド-N-20K PEG)]hGIP(1-43)-NH2(SEQ ID NO:48);もしくは
[A5c11, 41, Cys43(スクシンイミド-N-30K PEG)]hGIP(1-43)-NH2(SEQ ID NO:49);
である、請求項9に記載の化合物、またはその医薬的に許容できる塩。 [A5c 11, 41 , Cys 32 (succinimide-N-20K PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 46);
[A5c 11, 41 , Cys 33 (succinimide-N-20K PEG)] hGIP (1-42) -NH 2 (SEQ ID NO: 47);
[A5c 11, 41 , Cys 43 (succinimide-N-20K PEG)] hGIP (1-43) -NH 2 (SEQ ID NO: 48); or
[A5c 11, 41 , Cys 43 (succinimide-N-30K PEG)] hGIP (1-43) -NH 2 (SEQ ID NO: 49);
The compound according to claim 9 , or a pharmaceutically acceptable salt thereof.
またはその医薬的に許容できる塩である、請求項10に記載の化合物。 [A5c 11, 41 , Cys 43 (succinimide-N-30K PEG)] hGIP (1-43) -NH 2 (SEQ ID NO: 49);
11. The compound of claim 10 , which is or a pharmaceutically acceptable salt thereof.
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Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101417873B1 (en) | 2008-08-07 | 2014-07-09 | 입센 파마 에스.에이.에스 | Analogues of glucose-dependent insulinotropic polypeptide |
EA020005B1 (en) | 2008-08-07 | 2014-07-30 | Ипсен Фарма С.А.С. | Glucose-dependent insulinotropic polypeptide analogues |
WO2011018611A1 (en) * | 2009-08-10 | 2011-02-17 | Ucl Business Plc | Reversible covalent linkage of functional molecules |
DE102010015123A1 (en) | 2010-04-16 | 2011-10-20 | Sanofi-Aventis Deutschland Gmbh | New benzylamidic diphenylazetidinone compounds, useful for treating lipid disorders, hyperlipidemia, atherosclerotic manifestations or insulin resistance, and for reducing serum cholesterol levels |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
US9023986B2 (en) | 2010-10-25 | 2015-05-05 | Hoffmann-La Roche Inc. | Glucose-dependent insulinotropic peptide analogs |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
EP2567959B1 (en) | 2011-09-12 | 2014-04-16 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2013045413A1 (en) | 2011-09-27 | 2013-04-04 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
EP3530671A3 (en) | 2014-09-05 | 2019-11-13 | University of Copenhagen | Gip peptide analogues |
JOP20200119A1 (en) * | 2015-01-09 | 2017-06-16 | Lilly Co Eli | Gip and glp-1 co-agonist compounds |
CA3009650A1 (en) * | 2015-12-23 | 2017-06-29 | Amgen Inc. | Method of treating or ameliorating metabolic disorders using binding proteins for gastric inhibitory peptide receptor (gipr) in combination with glp-1 agonists |
JOP20190177A1 (en) | 2017-01-17 | 2019-07-16 | Amgen Inc | Method of treating or ameliorating metabolic disorders using glp-1 receptor agonists conjugated to antagonists for gastric inhibitory peptide receptor (gipr) |
JOP20180028A1 (en) | 2017-03-31 | 2019-01-30 | Takeda Pharmaceuticals Co | Peptide compound |
PL3630806T3 (en) | 2017-05-31 | 2024-05-13 | The University Of Copenhagen | Long-acting gip peptide analogues |
ES2961384T3 (en) | 2018-05-04 | 2024-03-11 | Novo Nordisk As | Derivatives of GIP and their uses |
Family Cites Families (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4562175A (en) | 1984-02-03 | 1985-12-31 | Ding Chang | Synthetic peptides |
DE69132708T2 (en) | 1990-09-24 | 2002-06-20 | Philadelphia Health And Education Corp., Philadelphia | Therapeutic use of peptides with thrombospondin-like activity |
JPH04145099A (en) * | 1990-10-05 | 1992-05-19 | Sanwa Kagaku Kenkyusho Co Ltd | Polypeptide derivative having gip-like activity and use thereof |
NZ250844A (en) * | 1993-04-07 | 1996-03-26 | Pfizer | Treatment of non-insulin dependant diabetes with peptides; composition |
US7091183B1 (en) * | 1996-12-03 | 2006-08-15 | Boston Medical Center Corporation | Specific antagonists for glucose-dependent insulinotropic polypeptide (GIP) |
AU5518798A (en) * | 1996-12-03 | 1998-06-29 | Trustees Of Boston University | Specific antagonists for glucose-dependent insulinotropic polypeptide (gip) |
CA2778047A1 (en) | 1998-12-07 | 2000-06-15 | Ipsen Pharma S.A.S | Analogues of glp-1 |
US6903186B1 (en) * | 1998-12-07 | 2005-06-07 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S | Analogues of GLP-1 |
GB0404124D0 (en) * | 2004-02-25 | 2004-03-31 | Univ Ulster | Antagonists of GIP |
US6921748B1 (en) * | 1999-03-29 | 2005-07-26 | Uutech Limited | Analogs of gastric inhibitory polypeptide and their use for treatment of diabetes |
US20050272652A1 (en) * | 1999-03-29 | 2005-12-08 | Gault Victor A | Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity |
US20040048248A1 (en) | 1999-10-05 | 2004-03-11 | Prayaga Sudhirdas K. | Endozepine-like polypeptides and polynucleotides encoding same |
EP1392484B1 (en) | 2001-04-06 | 2013-06-12 | California Institute Of Technology | High throughput screening of crystalization of materials |
TWI284539B (en) * | 2001-07-30 | 2007-08-01 | Epix Pharm Inc | A method for making a magnetic resonance (MR) imaging agent, a MR imaging contrast agent, a method for altering stability of a peptide and a modified peptide |
US20030232761A1 (en) | 2002-03-28 | 2003-12-18 | Hinke Simon A. | Novel analogues of glucose-dependent insulinotropic polypeptide |
CA2489323A1 (en) | 2002-06-15 | 2003-12-24 | Enteromed, Inc. | Treatment of non-alcoholic fatty liver disease |
EP2080521A1 (en) | 2002-10-22 | 2009-07-22 | Waratah Pharmaceuticals, Inc. | Gastrin compositions and formulations, and methods of use and preparation |
WO2004060966A2 (en) * | 2002-12-31 | 2004-07-22 | Nektar Therapeutics Al, Corporation | Maleamic acid polymer derivatives and their bioconjugates |
CN102174102A (en) | 2003-05-15 | 2011-09-07 | 塔夫茨大学信托人 | Stable analogs of peptide and polypeptide therapeutics |
WO2005047334A1 (en) | 2003-11-13 | 2005-05-26 | Hanmi Pharmaceutical. Co., Ltd. | Igg fc fragment for a drug carrier and method for the preparation thereof |
US7897566B2 (en) | 2003-12-16 | 2011-03-01 | Ipsen Pharma S.A.S. | Analogues of GLP-1 |
US8076288B2 (en) | 2004-02-11 | 2011-12-13 | Amylin Pharmaceuticals, Inc. | Hybrid polypeptides having glucose lowering activity |
TWI376234B (en) | 2005-02-01 | 2012-11-11 | Msd Oss Bv | Conjugates of a polypeptide and an oligosaccharide |
SG159551A1 (en) * | 2005-02-11 | 2010-03-30 | Amylin Pharmaceuticals Inc | Gip analog and hybrid polypeptides with selectable properties |
CN101155828A (en) * | 2005-02-11 | 2008-04-02 | 安米林药品公司 | Gip analog and hybrid polypeptides with selectable properties |
WO2006121904A1 (en) | 2005-05-06 | 2006-11-16 | Bayer Pharmaceuticals Corporation | Glucose-dependent insulinotropic polypeptide (gip) receptor agonists and their pharmacological methods of use |
US20090170762A1 (en) | 2005-09-08 | 2009-07-02 | Uutech Limited | Treatment of Diabetes Related Obesity |
EP1937716A2 (en) | 2005-09-08 | 2008-07-02 | Uutech Limited | Analogs of gastric inhibitory polypeptide as a treatment for age related decreased pancreatic beta cell function |
JPWO2007049695A1 (en) | 2005-10-26 | 2009-04-30 | 中外製薬株式会社 | Aggregating GLP-1 analog and sustained release pharmaceutical composition |
EP2057188B1 (en) | 2006-08-17 | 2013-07-31 | Amylin Pharmaceuticals, LLC | Dpp-iv resistant gip hybrid polypeptides with selectable properties |
JP2011530506A (en) | 2008-08-07 | 2011-12-22 | イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ | A truncated analog of a glucose-dependent insulinotropic polypeptide |
EA020005B1 (en) | 2008-08-07 | 2014-07-30 | Ипсен Фарма С.А.С. | Glucose-dependent insulinotropic polypeptide analogues |
KR101417873B1 (en) | 2008-08-07 | 2014-07-09 | 입센 파마 에스.에이.에스 | Analogues of glucose-dependent insulinotropic polypeptide |
AU2009280021B2 (en) | 2008-08-07 | 2012-10-04 | Ipsen Pharma S.A.S. | Analogues of glucose-dependent insulinotropic polypeptide (GIP) modified at N-terminal |
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US20110144007A1 (en) | 2011-06-16 |
JP2011530507A (en) | 2011-12-22 |
CN102170895A (en) | 2011-08-31 |
EP2323678A2 (en) | 2011-05-25 |
KR101593155B1 (en) | 2016-02-12 |
EP2323678A4 (en) | 2013-06-12 |
US20150252093A1 (en) | 2015-09-10 |
EA020005B1 (en) | 2014-07-30 |
AU2009280015A1 (en) | 2010-02-11 |
CA2732973A1 (en) | 2010-02-11 |
JP2014028843A (en) | 2014-02-13 |
EP2323678B1 (en) | 2016-03-23 |
WO2010016938A3 (en) | 2010-04-15 |
US9072703B2 (en) | 2015-07-07 |
MX2011001030A (en) | 2011-04-26 |
BRPI0917579A2 (en) | 2016-10-11 |
KR20110043688A (en) | 2011-04-27 |
ES2574835T3 (en) | 2016-06-22 |
AU2009280015B2 (en) | 2012-11-08 |
CN103641906A (en) | 2014-03-19 |
WO2010016938A2 (en) | 2010-02-11 |
KR20130133104A (en) | 2013-12-05 |
KR20150056667A (en) | 2015-05-26 |
HK1154790A1 (en) | 2012-05-04 |
EA201170303A1 (en) | 2011-10-31 |
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